Iddo Magen | Weizmann Institute of Science (original) (raw)

Papers by Iddo Magen

Brain Behavior and Immunity, Aug 1, 2022

BACKGROUND Both the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) hav... more BACKGROUND Both the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) have been proposed as biomarkers of suicidal risk in adults with depression. We examined whether these ratios may be considered biomarkers for suicidal behavior in young patients with major depressive or anxiety disorders before treatment with selective serotonin reuptake inhibitors (SSRIs), or as biomarkers for the adverse event of SSRI-associated suicidality. METHODS Children and adolescents meeting criteria for major depressive or anxiety disorder were recruited. Serum levels of three pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were assessed; and NLR and PLR calculated, from blood samples collected at baseline and after 8 weeks treatment with SSRI. A Mann-Whitney test was performed to evaluate differences in NLR and PLR between children with and without a history of a suicide attempt prior to treatment. We compared hematological parameters before and after treatment, and between children who developed SSRI-associated suicidality versus children without treatment emergent suicidality. RESULTS Among 91 children and adolescents (aged 13.9 ± 2.4 years), baseline NLR and PLR were significantly higher among those with a history of a suicide attempt versus those without such history. Statistically significant correlations were found for the suicide ideation subscale in the Columbia suicide severity rating scale with both baseline NLR and PLR. Baseline NLR and PLR were similar in children who did and did not develop SSRI-associated suicidality after 8 weeks. In the final logistic regression model (χ2=18.504, df=4, p value=0.001), after controlling for sex, depression severity and IL-6 levels, NLR was significantly associated with a past suicide attempt (β = 1.247, p = 0.019; OR [95% CI] = 3.478 [1.230-9.841]), with a NLR cut-off value of = 1.76 (area under the curve=0.75 (95% CI = 0.63-0.88, sensitivity = 73%, and specificity =71%, p value=0.003). CONCLUSIONS High NLR and PLR values may be associated with suicidal behavior in depressed and anxious children and adolescents. NLR appears as a better predictor of suicide attempt than PLR, and thus may be a useful biomarker of suicidality in young patients with depression or anxiety.

RNA Biology, Sep 18, 2018

In recent years, microRNAs (miRNAs) in tissues and biofluids have emerged as a new class of promi... more In recent years, microRNAs (miRNAs) in tissues and biofluids have emerged as a new class of promising biomarkers for numerous diseases. Blood-based biomarkers are particularly desirable since serum or plasma is easily accessible and can be sampled repeatedly. To comprehensively explore the biomarker potential of miRNAs, sensitive, accurate and cost-efficient miRNA profiling techniques are required. Next generation sequencing (NGS) is emerging as the preferred method for miRNA profiling; offering high sensitivity, singlenucleotide resolution and the possibility to profile a considerable number of samples in parallel. Despite the excitement about miRNA biomarkers, challenges associated with insufficient characterization of the sequencing library preparation efficacy, precision and method-related quantification bias have not been addressed in detail and are generally underappreciated in the wider research community. Here, we have tested in parallel four commercially available small RNA sequencing kits against a cohort of samples comprised of human plasma, human serum, murine brain tissue and a reference library containing~950 synthetic miRNAs. We discuss the advantages and limits of these methodologies for massive parallel microRNAs profiling. This work can serve as guideline for choosing an adequate library preparation method, based on sensitivity, specificity and accuracy of miRNA quantification, workflow convenience and potential for automation.

Journal of Parkinson's disease, Sep 14, 2015

Background: Patients with Parkinson's disease (PD) may exhibit deficits in "Theory of Mind", the ... more Background: Patients with Parkinson's disease (PD) may exhibit deficits in "Theory of Mind", the ability to read others' mental states and react appropriately, a prerequisite for successful social interaction. Alpha-synuclein overexpression is widely distributed in the brain of patients with sporadic PD, suggesting that it may contribute to the non-motor deficits observed in PD patients. Mice over-expressing human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSyn mice) have synaptic deficits in the frontostriatal pathway, low cortical acetylcholine, and high level of expression of mGluR5 receptors, which have all been implicated in social recognition deficits. Objective: To determine whether Thy1-aSyn mice present alterations in their response to social stimuli. Methods: We have submitted Thy1-aSyn mice to tests adapted from autism models. Results: At 7-8 month of age Thy1-aSyn mice explored their conspecifics significantly less than did wild-type littermates, without differences in exploration of inanimate objects, and pairs of Thy1-aSyn mice were involved in reciprocal interactions for a shorter duration than wild-type mice at this age. These deficits persisted when the test animal was enclosed in a beaker and were not present at 3-4 months of age despite the presence of olfactory deficits at that age, indicating that they were not solely caused by impairment in olfaction. Conclusion: Thy1-aSyn mice present progressive deficits in social recognition, supporting an association between alphasynuclein overexpression and Theory of Mind deficits in PD and providing a useful model for identifying mechanisms and testing novel treatments for these deficits which impact patients and caretakers quality of life.

Pharmacology Research & Perspectives, Aug 6, 2014

Gastroenterology, May 1, 2012

Current Medicinal Chemistry, Feb 17, 2014

This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an e... more This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in the laboratory of Prof. Illana Gozes. The effects of NAP and its related peptides in models of neurodegenerative diseases and other neurological disorders will be described here in details. Possible mechanisms of NAP actions include anti-inflammatory effect, antioxidant activity, inhibition of protein aggregation and interaction with microtubules. In line with the fact that all of these features are characteristic to most neurological/neurodegenerative disorders, NAP was found to have beneficial effects on the behavioral manifestations associated with these disorders.

Neuropeptides, Dec 1, 2013

This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an e... more This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in our laboratory. We have recently described the effects of NAP in neurodegenerative disorders, and we now review the beneficial effects of NAP and other microtubule-stabilizing agents on impairments in axonal transport. Experiments in animal models of microtubule-deficiency including tauopathy (spanning from drosophila to mammals) showed protection of axonal transport by microtubule-stabilizers and NAP, which was coupled to motor and cognitive protection. Clinical trials with NAP (davunetide) are reviewed paving the path to future developments.

Journal of Cardiac Surgery, Jun 2, 2020

Background: The aortic valve (AV) is the most commonly affected valve in valvular heart diseases ... more Background: The aortic valve (AV) is the most commonly affected valve in valvular heart diseases (VHDs). The objective of the study is to identify microRNA (miRNA) molecules expressed in VHDs and the differential expression patterns of miRNA in AVs with either calcification or rheumatism etiologies. Methods: Human AVs were collected during valve replacement surgery. RNA was extracted and miRNA containing libraries were prepared and sequenced using the next generation sequencing (NGS) approach. miRNAs identified as differentially expressed between the two etiologies were validated by quantitative real-time polymerase chain reaction (qPCR). The receiver operating characteristic (ROC) curve analysis was performed to examine the ability of relevant miRNA to differentiate between calcification and rheumatism etiologies. Results: Rheumatic and calcified AV samples were prepared for the NGS and were successfully sequenced. The expression was validated by the qPCR approach in 46 AVs, 13 rheumatic, and 33 calcified AVs, confirming that miR-145-5p, miR-199a-5p, and miR-5701 were significantly higher in rheumatic AVs as compared with calcified AVs. ROC curve analysis revealed that miR-145-5p had a sensitivity of 76.92% and a specificity of 94.12%, area under the curve (AUC) = 0.88 (P = .0001), and miR-5701 had a sensitivity of 84.62% and a specificity of 76.47%, AUC = 0.78 (P = .0001), whereas miR-199a-5p had a sensitivity of 84.62%, and a specificity of 57.58%, AUC = 0.73 (P = .0083). Conclusion: We documented differential miRNA expression between AV disease etiologies. The miRNAs identified in this study advance our understanding of the mechanisms underlining AV disease.

European Journal of Neurology, Jun 7, 2022

Background and purposeThe antisense oligonucleotide nusinersen (Spinraza) regulates splicing of t... more Background and purposeThe antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator‐free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients.MethodsThirty‐four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively.ResultsLower baseline levels of two muscle microRNAs (miR‐206 and miR‐133a‐3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR‐206 levels were inversely correlated with the HFMSE score.ConclusionsLower miR‐206 and miR‐133a‐3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long‐term benefit.

Journal of Parkinson's disease, 2011

Synucleopathies are neurodegenerative disorders characterized by abnormal accumulation of alpha-s... more Synucleopathies are neurodegenerative disorders characterized by abnormal accumulation of alpha-synuclein, most often in neurons. Familial forms are due to mutations or multiplications of the gene encoding for alpha-synuclein but most synucleopathies occur sporadically. They include Parkinson's disease (PD) and dementia with Lewy Bodies (DLB), which are both linked to cognitive decline. In DLB, dementia dominates the symptoms whereas in PD, subtle cognitive deficits are frequent and may appear even before motor symptoms, but only a fraction of patients develop severe dementia-type cognitive deficits. Several lines of mice were developed to model human synucleopathies by over-expressing the wild type or the mutated human alpha-synuclein under a variety of promoters. In addition, mice lacking alpha-synuclein have been used to determine the role of this protein in cognitive function. This chapter will review cognitive alterations observed in these models and discuss how they may help understand the various forms and stages of cognitive deficits observed in patients with synucleopathies.

Neurobiology of Disease, Sep 1, 2018

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer fro... more In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice overexpressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Scientific Reports, Mar 16, 2017

Amyotrophic lateral sclerosis (ALS) is a multifactorial lethal motor neuron disease with no known... more Amyotrophic lateral sclerosis (ALS) is a multifactorial lethal motor neuron disease with no known treatment. Although the basic mechanism of its degenerative pathogenesis remains poorly understood, a subcellular spatial alteration in RNA metabolism is thought to play a key role. The nature of these RNAs remains elusive, and a comprehensive characterization of the axonal RNAs involved in maintaining neuronal health has yet to be described. Here, using cultured spinal cord (SC) neurons grown using a compartmented platform followed by next-generation sequencing (NGS) technology, we find that RNA expression differs between the somatic and axonal compartments of the neuron, for both mRNA and microRNA (miRNA). Further, the introduction of SOD1 G93A and TDP43 A315T , established ALSrelated mutations, changed the subcellular expression and localization of RNAs within the neurons, showing a spatial specificity to either the soma or the axon. Altogether, we provide here the first combined inclusive profile of mRNA and miRNA expression in two ALS models at the subcellular level. These data provide an important resource for studies on the roles of local protein synthesis and axon degeneration in ALS and can serve as a possible target pool for ALS treatment. The subcellular proteome is closely regulated in order to respond to extrinsic signals and metabolic demands 1,2. In neurons, which are highly polarized cells, localization of mRNAs and miRNAs together with local synthesis events at distinct subcellular compartments, such as the soma, dendrites, axons and synapses, can control the subcellular proteome and thus can facilitate the neurons' ability to respond to stress 3-5. Alterations in this process can lead to diverse pathological events in the neurons. Indeed, alterations in subcellular localization of RNA binding proteins was demonstrated in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) 6-9. This suggests the existence of alterations in ALS subcellular transcriptomes; however, the identity and nature of these RNAs remain unknown. The introduction of next-generation sequencing (NGS) techniques combined with subcellular fractionation enables a wide yet precise view of the subcellular transcriptome, which was previously unattainable. ALS is a lethal, adult-onset neurodegenerative disease that affects both upper and lower motor neurons 10. ALS pathology is characterized by neuromuscular junction (NMJ) disruption, axonal degeneration, and neuronal death 11. One of the mechanisms suggested to initiate ALS cellular pathology is an alteration in RNA metabolism, specifically alterations in subcellular localization of RNA 7,10,12,13. This hypothesis is reinforced by emerging research implicating diverse aspects of RNA processing in a broad spectrum of neurodegenerative diseases 14,15. Previous research highlighted several related dysfunctions in ALS that further support this notion: axonal transport deficit 16-18 , mutations in RNA binding protein (RBP) 19,20 ; and dysregulation of mRNA 21 and microRNA (miRNA) 22-24. miRNAs participate in the regulation of gene expression in many, possibly all, biological processes, and their dysregulation would be predicted to have broad implications. miRNAs act by binding to their target mRNAs, resulting in translational repression and/or mRNA degradation 25. As miRNAs can potentially be used

Elsevier eBooks, 2010

The identification of several mutations causing familial forms of Parkinson&a... more The identification of several mutations causing familial forms of Parkinson's disease (PD) has led to the creation of multiple lines of mice expressing similar genetic alterations. These models present a unique opportunity for understanding pathophysiological mechanisms leading to PD in a mammalian brain and provide models that are suitable for the preclinical testing of new therapies. Different lines of mice recapitulate the symptoms and pathological features of PD to various extents. This chapter examines their respective advantages and highlights some of the key findings that have already emerged from the analysis of these new models of PD.

Neuromuscular Disorders, Oct 1, 2022

Cambridge University Press eBooks, Oct 8, 2014

Neurotherapeutics, Feb 15, 2012

Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subseq... more Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subsequent studies of genetic risk factors for sporadic PD have led to an improved understanding of the pathological mechanisms that may cause nonfamilial PD. In particular, genetic and pathological studies strongly suggest that alpha-synuclein, albeit very rarely mutated in PD patients, plays a critical role in the vast majority of individuals with the sporadic form of the disease. We have extensively characterized a mouse model over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter. We have also shown that this model reproduces many features of sporadic PD, including progressive changes in dopamine release and striatal content, alphasynuclein pathology, deficits in motor and nonmotor functions that are affected in pre-manifest and manifest phases of PD, inflammation, and biochemical and molecular changes similar to those observed in PD. Preclinical studies have already demonstrated improvement with promising new drugs in this model, which provides an opportunity to test novel neuroprotective strategies during different phases of the disorder using endpoint measures with high power to detect drug effects.

Neurotherapeutics, Jun 5, 2017

Aberrant accumulation and self-assembly of αsynuclein are tightly linked to several neurodegenera... more Aberrant accumulation and self-assembly of αsynuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar α-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble α-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic αsynuclein assemblies are attractive for these incurable disorders. The Bmolecular tweezer^CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type α-synuclein under control of the Thy-1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and α-synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble α-synuclein in the striatum. Proteinase-K-resistant, insoluble α-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic α-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies.

Neuropathology and Applied Neurobiology

AimsThis study aimed to explore the non‐linear relationships between cell‐free microRNAs (miRNAs)... more AimsThis study aimed to explore the non‐linear relationships between cell‐free microRNAs (miRNAs) and their contribution to prediction of Frontotemporal dementia (FTD), an early onset dementia that is clinically heterogeneous, and too often suffers from delayed diagnosis.MethodsWe initially studied a training cohort of 219 subjects (135 FTD and 84 non‐neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls).ResultsOn the basis of cell‐free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a non‐linear prediction model that accurately distinguishes FTD from non‐neurodegenerative controls in ~90% of cases.ConclusionsThe fascinating potential of diagnostic miRNA biomarkers might enable early‐stage detection and a cost‐effective screening approach for clinical trials that can facilitate drug development.

La presente invention concerne les composes D9-tetrahydrocannabinol (THC), cannabidiol (CBD) et c... more La presente invention concerne les composes D9-tetrahydrocannabinol (THC), cannabidiol (CBD) et capsaicine utilisables pour la prevention ou le traitement, ou les deux, de l'encephalopathie hepatique. Les composes capsaicine, 2-arachidonoylglycerol (2-AG), HU-308 et cannabidiol sont utilisables pour la prevention ou le traitement, ou les deux, de la cirrhose du foie.

Brain Research, 2017

We have investigated the effects of 0.001 mg/kg 2-arachidonoylglycerol (2-AG) administered in com... more We have investigated the effects of 0.001 mg/kg 2-arachidonoylglycerol (2-AG) administered in combination with compounds present in the body alongside 2-AG like 2-palmitoylglycerol and 2-linoleylglycerol (also termed ''entourage"), on cognitive function,food intake, and neurotransmitter levels in the hippocampus and hypothalamus of mice under diet restriction. Young female Sabra mice were treated with vehicle, 2-AG, 2-AG + entourage, 2-AG + entourage + 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4methyl-N-(piperidin-1-yl)-1 H-pyrazole-3-carboxamide (SR141716A, a CB 1 antagonist) and SR141716A. The mice were fed for 2.5 h a day for 14 days. Cognitive function was evaluated by the eight arm maze test, and neurotransmitter (norepinephrine, dopamine, L-DOPA and serotonin) levels were measured in the hippocampus and hypothalamus by high-performance liquid chromatography-electrochemical detection. Food intake was increased by 2-AG and, to an even greater extent, by 2-AG + entourage. SR141716A reversed the effect of 2-AG + entourage. The administration of 2-AG + entourage improved cognitive function compared to the vehicle mice, and this improvement was blocked by SR141716A. 2-AG + entourage-treated mice showed an increase in norepinephrine (NE), dopamine and L-DOPA levels in the hippocampus. SR141716A normalized NE and L-DOPA levels. There were no significant changes in hypothalamic neurotransmitter levels. The use of very low doses of the endocannabinoid 2-AG + entourage can improve cognitive function by elevating norepinephrine and L-DOPA levels in the hippocampus, without cannabinomimetic side effects. These findings may have implications for cognitive enhancement in anorexia nervosa.

Brain Behavior and Immunity, Aug 1, 2022

BACKGROUND Both the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) hav... more BACKGROUND Both the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) have been proposed as biomarkers of suicidal risk in adults with depression. We examined whether these ratios may be considered biomarkers for suicidal behavior in young patients with major depressive or anxiety disorders before treatment with selective serotonin reuptake inhibitors (SSRIs), or as biomarkers for the adverse event of SSRI-associated suicidality. METHODS Children and adolescents meeting criteria for major depressive or anxiety disorder were recruited. Serum levels of three pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were assessed; and NLR and PLR calculated, from blood samples collected at baseline and after 8 weeks treatment with SSRI. A Mann-Whitney test was performed to evaluate differences in NLR and PLR between children with and without a history of a suicide attempt prior to treatment. We compared hematological parameters before and after treatment, and between children who developed SSRI-associated suicidality versus children without treatment emergent suicidality. RESULTS Among 91 children and adolescents (aged 13.9 ± 2.4 years), baseline NLR and PLR were significantly higher among those with a history of a suicide attempt versus those without such history. Statistically significant correlations were found for the suicide ideation subscale in the Columbia suicide severity rating scale with both baseline NLR and PLR. Baseline NLR and PLR were similar in children who did and did not develop SSRI-associated suicidality after 8 weeks. In the final logistic regression model (χ2=18.504, df=4, p value=0.001), after controlling for sex, depression severity and IL-6 levels, NLR was significantly associated with a past suicide attempt (β = 1.247, p = 0.019; OR [95% CI] = 3.478 [1.230-9.841]), with a NLR cut-off value of = 1.76 (area under the curve=0.75 (95% CI = 0.63-0.88, sensitivity = 73%, and specificity =71%, p value=0.003). CONCLUSIONS High NLR and PLR values may be associated with suicidal behavior in depressed and anxious children and adolescents. NLR appears as a better predictor of suicide attempt than PLR, and thus may be a useful biomarker of suicidality in young patients with depression or anxiety.

RNA Biology, Sep 18, 2018

In recent years, microRNAs (miRNAs) in tissues and biofluids have emerged as a new class of promi... more In recent years, microRNAs (miRNAs) in tissues and biofluids have emerged as a new class of promising biomarkers for numerous diseases. Blood-based biomarkers are particularly desirable since serum or plasma is easily accessible and can be sampled repeatedly. To comprehensively explore the biomarker potential of miRNAs, sensitive, accurate and cost-efficient miRNA profiling techniques are required. Next generation sequencing (NGS) is emerging as the preferred method for miRNA profiling; offering high sensitivity, singlenucleotide resolution and the possibility to profile a considerable number of samples in parallel. Despite the excitement about miRNA biomarkers, challenges associated with insufficient characterization of the sequencing library preparation efficacy, precision and method-related quantification bias have not been addressed in detail and are generally underappreciated in the wider research community. Here, we have tested in parallel four commercially available small RNA sequencing kits against a cohort of samples comprised of human plasma, human serum, murine brain tissue and a reference library containing~950 synthetic miRNAs. We discuss the advantages and limits of these methodologies for massive parallel microRNAs profiling. This work can serve as guideline for choosing an adequate library preparation method, based on sensitivity, specificity and accuracy of miRNA quantification, workflow convenience and potential for automation.

Journal of Parkinson's disease, Sep 14, 2015

Background: Patients with Parkinson's disease (PD) may exhibit deficits in "Theory of Mind", the ... more Background: Patients with Parkinson's disease (PD) may exhibit deficits in "Theory of Mind", the ability to read others' mental states and react appropriately, a prerequisite for successful social interaction. Alpha-synuclein overexpression is widely distributed in the brain of patients with sporadic PD, suggesting that it may contribute to the non-motor deficits observed in PD patients. Mice over-expressing human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSyn mice) have synaptic deficits in the frontostriatal pathway, low cortical acetylcholine, and high level of expression of mGluR5 receptors, which have all been implicated in social recognition deficits. Objective: To determine whether Thy1-aSyn mice present alterations in their response to social stimuli. Methods: We have submitted Thy1-aSyn mice to tests adapted from autism models. Results: At 7-8 month of age Thy1-aSyn mice explored their conspecifics significantly less than did wild-type littermates, without differences in exploration of inanimate objects, and pairs of Thy1-aSyn mice were involved in reciprocal interactions for a shorter duration than wild-type mice at this age. These deficits persisted when the test animal was enclosed in a beaker and were not present at 3-4 months of age despite the presence of olfactory deficits at that age, indicating that they were not solely caused by impairment in olfaction. Conclusion: Thy1-aSyn mice present progressive deficits in social recognition, supporting an association between alphasynuclein overexpression and Theory of Mind deficits in PD and providing a useful model for identifying mechanisms and testing novel treatments for these deficits which impact patients and caretakers quality of life.

Pharmacology Research & Perspectives, Aug 6, 2014

Gastroenterology, May 1, 2012

Current Medicinal Chemistry, Feb 17, 2014

This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an e... more This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in the laboratory of Prof. Illana Gozes. The effects of NAP and its related peptides in models of neurodegenerative diseases and other neurological disorders will be described here in details. Possible mechanisms of NAP actions include anti-inflammatory effect, antioxidant activity, inhibition of protein aggregation and interaction with microtubules. In line with the fact that all of these features are characteristic to most neurological/neurodegenerative disorders, NAP was found to have beneficial effects on the behavioral manifestations associated with these disorders.

Neuropeptides, Dec 1, 2013

This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an e... more This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in our laboratory. We have recently described the effects of NAP in neurodegenerative disorders, and we now review the beneficial effects of NAP and other microtubule-stabilizing agents on impairments in axonal transport. Experiments in animal models of microtubule-deficiency including tauopathy (spanning from drosophila to mammals) showed protection of axonal transport by microtubule-stabilizers and NAP, which was coupled to motor and cognitive protection. Clinical trials with NAP (davunetide) are reviewed paving the path to future developments.

Journal of Cardiac Surgery, Jun 2, 2020

Background: The aortic valve (AV) is the most commonly affected valve in valvular heart diseases ... more Background: The aortic valve (AV) is the most commonly affected valve in valvular heart diseases (VHDs). The objective of the study is to identify microRNA (miRNA) molecules expressed in VHDs and the differential expression patterns of miRNA in AVs with either calcification or rheumatism etiologies. Methods: Human AVs were collected during valve replacement surgery. RNA was extracted and miRNA containing libraries were prepared and sequenced using the next generation sequencing (NGS) approach. miRNAs identified as differentially expressed between the two etiologies were validated by quantitative real-time polymerase chain reaction (qPCR). The receiver operating characteristic (ROC) curve analysis was performed to examine the ability of relevant miRNA to differentiate between calcification and rheumatism etiologies. Results: Rheumatic and calcified AV samples were prepared for the NGS and were successfully sequenced. The expression was validated by the qPCR approach in 46 AVs, 13 rheumatic, and 33 calcified AVs, confirming that miR-145-5p, miR-199a-5p, and miR-5701 were significantly higher in rheumatic AVs as compared with calcified AVs. ROC curve analysis revealed that miR-145-5p had a sensitivity of 76.92% and a specificity of 94.12%, area under the curve (AUC) = 0.88 (P = .0001), and miR-5701 had a sensitivity of 84.62% and a specificity of 76.47%, AUC = 0.78 (P = .0001), whereas miR-199a-5p had a sensitivity of 84.62%, and a specificity of 57.58%, AUC = 0.73 (P = .0083). Conclusion: We documented differential miRNA expression between AV disease etiologies. The miRNAs identified in this study advance our understanding of the mechanisms underlining AV disease.

European Journal of Neurology, Jun 7, 2022

Background and purposeThe antisense oligonucleotide nusinersen (Spinraza) regulates splicing of t... more Background and purposeThe antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator‐free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients.MethodsThirty‐four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively.ResultsLower baseline levels of two muscle microRNAs (miR‐206 and miR‐133a‐3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR‐206 levels were inversely correlated with the HFMSE score.ConclusionsLower miR‐206 and miR‐133a‐3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long‐term benefit.

Journal of Parkinson's disease, 2011

Synucleopathies are neurodegenerative disorders characterized by abnormal accumulation of alpha-s... more Synucleopathies are neurodegenerative disorders characterized by abnormal accumulation of alpha-synuclein, most often in neurons. Familial forms are due to mutations or multiplications of the gene encoding for alpha-synuclein but most synucleopathies occur sporadically. They include Parkinson's disease (PD) and dementia with Lewy Bodies (DLB), which are both linked to cognitive decline. In DLB, dementia dominates the symptoms whereas in PD, subtle cognitive deficits are frequent and may appear even before motor symptoms, but only a fraction of patients develop severe dementia-type cognitive deficits. Several lines of mice were developed to model human synucleopathies by over-expressing the wild type or the mutated human alpha-synuclein under a variety of promoters. In addition, mice lacking alpha-synuclein have been used to determine the role of this protein in cognitive function. This chapter will review cognitive alterations observed in these models and discuss how they may help understand the various forms and stages of cognitive deficits observed in patients with synucleopathies.

Neurobiology of Disease, Sep 1, 2018

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer fro... more In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice overexpressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Scientific Reports, Mar 16, 2017

Amyotrophic lateral sclerosis (ALS) is a multifactorial lethal motor neuron disease with no known... more Amyotrophic lateral sclerosis (ALS) is a multifactorial lethal motor neuron disease with no known treatment. Although the basic mechanism of its degenerative pathogenesis remains poorly understood, a subcellular spatial alteration in RNA metabolism is thought to play a key role. The nature of these RNAs remains elusive, and a comprehensive characterization of the axonal RNAs involved in maintaining neuronal health has yet to be described. Here, using cultured spinal cord (SC) neurons grown using a compartmented platform followed by next-generation sequencing (NGS) technology, we find that RNA expression differs between the somatic and axonal compartments of the neuron, for both mRNA and microRNA (miRNA). Further, the introduction of SOD1 G93A and TDP43 A315T , established ALSrelated mutations, changed the subcellular expression and localization of RNAs within the neurons, showing a spatial specificity to either the soma or the axon. Altogether, we provide here the first combined inclusive profile of mRNA and miRNA expression in two ALS models at the subcellular level. These data provide an important resource for studies on the roles of local protein synthesis and axon degeneration in ALS and can serve as a possible target pool for ALS treatment. The subcellular proteome is closely regulated in order to respond to extrinsic signals and metabolic demands 1,2. In neurons, which are highly polarized cells, localization of mRNAs and miRNAs together with local synthesis events at distinct subcellular compartments, such as the soma, dendrites, axons and synapses, can control the subcellular proteome and thus can facilitate the neurons' ability to respond to stress 3-5. Alterations in this process can lead to diverse pathological events in the neurons. Indeed, alterations in subcellular localization of RNA binding proteins was demonstrated in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) 6-9. This suggests the existence of alterations in ALS subcellular transcriptomes; however, the identity and nature of these RNAs remain unknown. The introduction of next-generation sequencing (NGS) techniques combined with subcellular fractionation enables a wide yet precise view of the subcellular transcriptome, which was previously unattainable. ALS is a lethal, adult-onset neurodegenerative disease that affects both upper and lower motor neurons 10. ALS pathology is characterized by neuromuscular junction (NMJ) disruption, axonal degeneration, and neuronal death 11. One of the mechanisms suggested to initiate ALS cellular pathology is an alteration in RNA metabolism, specifically alterations in subcellular localization of RNA 7,10,12,13. This hypothesis is reinforced by emerging research implicating diverse aspects of RNA processing in a broad spectrum of neurodegenerative diseases 14,15. Previous research highlighted several related dysfunctions in ALS that further support this notion: axonal transport deficit 16-18 , mutations in RNA binding protein (RBP) 19,20 ; and dysregulation of mRNA 21 and microRNA (miRNA) 22-24. miRNAs participate in the regulation of gene expression in many, possibly all, biological processes, and their dysregulation would be predicted to have broad implications. miRNAs act by binding to their target mRNAs, resulting in translational repression and/or mRNA degradation 25. As miRNAs can potentially be used

Elsevier eBooks, 2010

The identification of several mutations causing familial forms of Parkinson&a... more The identification of several mutations causing familial forms of Parkinson's disease (PD) has led to the creation of multiple lines of mice expressing similar genetic alterations. These models present a unique opportunity for understanding pathophysiological mechanisms leading to PD in a mammalian brain and provide models that are suitable for the preclinical testing of new therapies. Different lines of mice recapitulate the symptoms and pathological features of PD to various extents. This chapter examines their respective advantages and highlights some of the key findings that have already emerged from the analysis of these new models of PD.

Neuromuscular Disorders, Oct 1, 2022

Cambridge University Press eBooks, Oct 8, 2014

Neurotherapeutics, Feb 15, 2012

Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subseq... more Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subsequent studies of genetic risk factors for sporadic PD have led to an improved understanding of the pathological mechanisms that may cause nonfamilial PD. In particular, genetic and pathological studies strongly suggest that alpha-synuclein, albeit very rarely mutated in PD patients, plays a critical role in the vast majority of individuals with the sporadic form of the disease. We have extensively characterized a mouse model over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter. We have also shown that this model reproduces many features of sporadic PD, including progressive changes in dopamine release and striatal content, alphasynuclein pathology, deficits in motor and nonmotor functions that are affected in pre-manifest and manifest phases of PD, inflammation, and biochemical and molecular changes similar to those observed in PD. Preclinical studies have already demonstrated improvement with promising new drugs in this model, which provides an opportunity to test novel neuroprotective strategies during different phases of the disorder using endpoint measures with high power to detect drug effects.

Neurotherapeutics, Jun 5, 2017

Aberrant accumulation and self-assembly of αsynuclein are tightly linked to several neurodegenera... more Aberrant accumulation and self-assembly of αsynuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar α-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble α-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic αsynuclein assemblies are attractive for these incurable disorders. The Bmolecular tweezer^CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type α-synuclein under control of the Thy-1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and α-synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble α-synuclein in the striatum. Proteinase-K-resistant, insoluble α-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic α-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies.

Neuropathology and Applied Neurobiology

AimsThis study aimed to explore the non‐linear relationships between cell‐free microRNAs (miRNAs)... more AimsThis study aimed to explore the non‐linear relationships between cell‐free microRNAs (miRNAs) and their contribution to prediction of Frontotemporal dementia (FTD), an early onset dementia that is clinically heterogeneous, and too often suffers from delayed diagnosis.MethodsWe initially studied a training cohort of 219 subjects (135 FTD and 84 non‐neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls).ResultsOn the basis of cell‐free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a non‐linear prediction model that accurately distinguishes FTD from non‐neurodegenerative controls in ~90% of cases.ConclusionsThe fascinating potential of diagnostic miRNA biomarkers might enable early‐stage detection and a cost‐effective screening approach for clinical trials that can facilitate drug development.

La presente invention concerne les composes D9-tetrahydrocannabinol (THC), cannabidiol (CBD) et c... more La presente invention concerne les composes D9-tetrahydrocannabinol (THC), cannabidiol (CBD) et capsaicine utilisables pour la prevention ou le traitement, ou les deux, de l'encephalopathie hepatique. Les composes capsaicine, 2-arachidonoylglycerol (2-AG), HU-308 et cannabidiol sont utilisables pour la prevention ou le traitement, ou les deux, de la cirrhose du foie.

Brain Research, 2017

We have investigated the effects of 0.001 mg/kg 2-arachidonoylglycerol (2-AG) administered in com... more We have investigated the effects of 0.001 mg/kg 2-arachidonoylglycerol (2-AG) administered in combination with compounds present in the body alongside 2-AG like 2-palmitoylglycerol and 2-linoleylglycerol (also termed ''entourage"), on cognitive function,food intake, and neurotransmitter levels in the hippocampus and hypothalamus of mice under diet restriction. Young female Sabra mice were treated with vehicle, 2-AG, 2-AG + entourage, 2-AG + entourage + 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4methyl-N-(piperidin-1-yl)-1 H-pyrazole-3-carboxamide (SR141716A, a CB 1 antagonist) and SR141716A. The mice were fed for 2.5 h a day for 14 days. Cognitive function was evaluated by the eight arm maze test, and neurotransmitter (norepinephrine, dopamine, L-DOPA and serotonin) levels were measured in the hippocampus and hypothalamus by high-performance liquid chromatography-electrochemical detection. Food intake was increased by 2-AG and, to an even greater extent, by 2-AG + entourage. SR141716A reversed the effect of 2-AG + entourage. The administration of 2-AG + entourage improved cognitive function compared to the vehicle mice, and this improvement was blocked by SR141716A. 2-AG + entourage-treated mice showed an increase in norepinephrine (NE), dopamine and L-DOPA levels in the hippocampus. SR141716A normalized NE and L-DOPA levels. There were no significant changes in hypothalamic neurotransmitter levels. The use of very low doses of the endocannabinoid 2-AG + entourage can improve cognitive function by elevating norepinephrine and L-DOPA levels in the hippocampus, without cannabinomimetic side effects. These findings may have implications for cognitive enhancement in anorexia nervosa.