patrick pierre michel - Academia.edu (original) (raw)

Papers by patrick pierre michel

Doxycycline is a tetracycline commonly used for its antibiotic properties and capacity to treat a... more Doxycycline is a tetracycline commonly used for its antibiotic properties and capacity to treat acne- and rosacea-like skin lesions. It has also recently demonstrated interesting effects against Parkinson's disease pathomechanisms. Notably, doxycycline was reported to limit amyloid-type aggregation of α-synuclein and curtail neurodegeneration-related inflammatory processes. However, the potential therapeutic interest of doxycycline is limited due to its antibiotic activity. The design of novel doxycycline derivatives was undertaken to generate non-antimicrobial doxycycline derivatives with still neuroprotective properties. Specifically, the dimethyl-amino at C4 group was reduced to significantly diminish the antibiotic activity, and several coupling reactions were performed at position C9 of the D ring. Among 18 novel tetracyclines, seven derivatives with reduced antibiotic activity were more efficient than their parent compound in reducing α-synuclein aggregation. Among those, ...

Movement Disorders

BackgroundHigh consumption of Annona muricata fruit has been previously identified as a risk fact... more BackgroundHigh consumption of Annona muricata fruit has been previously identified as a risk factor for atypical parkinsonism in the French Caribbean islands.ObjectiveWe tested whether consumption of Annonaceae products could worsen the clinical phenotype of patients with any form of degenerative parkinsonism.MethodsWe analyzed neurological data from 180 Caribbean parkinsonian patients and specifically looked for dose effects of lifelong, cumulative Annonaceae consumption on cognitive performance. Using unsupervised clustering, we identified one cluster with mild/moderate symptoms (N = 102) and one with severe symptoms including cognitive impairment (N = 78).ResultsWe showed that even low cumulative consumption of fruits/juices (>0.2 fruit‐years) or any consumption of herbal tea from Annonaceae worsen disease severity and cognitive deficits in degenerative parkinsonism including Parkinson's disease (OR fruits‐juices: 3.76 [95% CI: 1.13–15.18]; OR herbal tea: 2.91 [95% CI: 1.3...

Background: Mechanisms underlying acute brain injury in SARS-CoV-2 patients remain poorly underst... more Background: Mechanisms underlying acute brain injury in SARS-CoV-2 patients remain poorly understood. A better characterization of such mechanisms remains essential to preventing long-term neurological sequelae. Our present aim was to study a panel of biomarkers of neuroinflammation and neurodegeneration in the cerebrospinal fluid (CSF) of NeuroCOVID patients.Methods: We retrospectively collected clinical and CSF biomarkers data from 24 NeuroCOVID adults seen at the University Hospital of Guadeloupe between March and June 2021.Results: Among 24 NeuroCOVID patients, 71% had encephalopathy and 29% a meningoencephalitis. A number of these patients also experienced de novo movement disorder (33%) or stroke (21%). The CSF analysis revealed intrathecal immunoglobulin synthesis in 54% of NeuroCOVID patients (two with a type 2 pattern and 11 with a type 3) and elevated neopterin levels in 75% of them (median 9.1 nM, IQR 5.6-22.1). CSF neurofilament light chain (NfL) was also increased compa...

Cells

To model α-Synuclein (αS) aggregation and neurodegeneration in Parkinson’s disease (PD), we estab... more To model α-Synuclein (αS) aggregation and neurodegeneration in Parkinson’s disease (PD), we established cultures of mouse midbrain dopamine (DA) neurons and chronically exposed them to fibrils 91 (F91) generated from recombinant human αS. We found that F91 have an exquisite propensity to seed the aggregation of endogenous αS in DA neurons when compared to other neurons in midbrain cultures. Until two weeks post-exposure, somal aggregation in DA neurons increased with F91 concentrations (0.01–0.75 μM) and the time elapsed since the initiation of seeding, with, however, no evidence of DA cell loss within this time interval. Neither toxin-induced mitochondrial deficits nor genetically induced loss of mitochondrial quality control mechanisms promoted F91-mediated αS aggregation or neurodegeneration under these conditions. Yet, a significant loss of DA neurons (~30%) was detectable three weeks after exposure to F91 (0.5 μM), i.e., at a time point where somal aggregation reached a plateau...

Tetracyclines have recently emerged as possible therapeutic agents for several diseases of the ce... more Tetracyclines have recently emerged as possible therapeutic agents for several diseases of the central nervous system. Chemically modified tetracycline 3 (also known as Incyclinide, CMT-3 or COL-3), a tetracycline derivative without antibiotic activity that crosses the blood-brain barrier, has been recently validated as a potent anti-inflammatory molecule. The present study discloses a possible mechanism through which COL-3 induces an anti-inflammatory response in cultured microglial cells activated by two different inflammogens: the standard bacterial component lipopolysaccharide (LPS) and the amyloid fibrils of the synaptic protein α-Synuclein (αSa). Under LPS and αSa treatment, COL-3 effectively reduced the production of prototypical

Scientific Reports, 2020

Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote s... more Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote synaptic development and functions by connecting various synaptic adhesion proteins (AP). HS binding to AP could vary according to modifications of HS chains by different sulfotransferases. 3-O-sulfotransferases (Hs3sts) produce rare 3-O-sulfated HSs (3S-HSs), of poorly known functions in the nervous system. Here, we showed that a peptide known to block herpes simplex virus by interfering with 3S-HSs in vitro and in vivo (i.e. G2 peptide), specifically inhibited neural activity, reduced evoked glutamate release, and impaired synaptic assembly in hippocampal cell cultures. A role for 3S-HSs in promoting synaptic assembly and neural activity is consistent with the synaptic interactome of G2 peptide, and with the detection of Hs3sts and their products in synapses of cultured neurons and in synaptosomes prepared from developing brains. Our study suggests that 3S-HSs acting as receptors for he...

Molecular Pharmacology, 2018

European Respiratory Journal, 2019

Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading... more Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (https://clinicaltrials.gov;NCT01583088). Myofibre type, size and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed using multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity (VC), maximal inspiratory pressure, sniff nasal inspiratory pressure (SNIP) and twitch transdiaphragma...

Neuron, May 18, 2016

Parkinson disease (PD) is a multifactorial neurodegenerative disorder, the etiology of which rema... more Parkinson disease (PD) is a multifactorial neurodegenerative disorder, the etiology of which remains largely unknown. Progressive impairment of voluntary motor control, which represents the primary clinical feature of the disease, is caused by a loss of midbrain substantia nigra dopamine (DA) neurons. We present here a synthetic overview of cell-autonomous mechanisms that are likely to participate in DA cell death in both sporadic and inherited forms of the disease. In particular, we describe how damage to vulnerable DA neurons may arise from cellular disturbances produced by protein misfolding and aggregation, disruption of autophagic catabolism, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, or loss of calcium homeostasis. Where pertinent, we show how these mechanisms may mutually cooperate to promote neuronal death.

Human Molecular Genetics, 2016

Mutations in PARK2, encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autoso... more Mutations in PARK2, encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autosomal recessive Parkinson's disease (PD). Loss of PARK2 function compromises mitochondrial quality by affecting mitochondrial biogenesis, bioenergetics, dynamics, transport and turnover. We investigated the impact of PARK2 dysfunction on the endoplasmic reticulum (ER)-mitochondria interface, which mediates Ca 2+ exchange between the two compartments and is essential for Parkindependent mitophagy. Confocal and electron microscopy analyses showed the ER and mitochondria to be in closer proximity in primary fibroblasts from PARK2 KO mice and PD patients with PARK2 mutations than in controls. Ca 2+ flux to the cytosol was also modified, due to enhanced ER-tomitochondria Ca 2+ transfers, a change that was also observed in neurons derived from induced pluripotent stem cells of a patient with PARK2 mutations. Subcellular fractionation showed the abundance of the Parkin substrate mitofusin 2 (Mfn2), which is known to modulate the ERmitochondria interface, to be specifically higher in the mitochondrion-associated ER membrane compartment in PARK2 KO tissue. Mfn2 downregulation or the exogenous expression of normal Parkin restored cytosolic Ca 2+ transients in fibroblasts from patients with PARK2 mutations. By contrast, a catalytically inactive PD-related Parkin variant had no effect. Overall, our data suggest that Parkin is directly involved in regulating ER-mitochondria contacts and provide new insight into the role of the loss of Parkin function in PD development.

Histology and histopathology, 1997

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive cell lo... more Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive cell loss confined mostly to dopaminergic neurons of the substantia nigra. Several factors, including oxidative stress, and decreased activity of complex I mitochondrial respiratory chain, are involved in the degenerative process. Yet, the underlying mechanisms leading to dopaminergic cell loss remain elusive. Morphological assessment for different modes of cell death: apoptosis, necrosis or autophagic degeneration, can contribute significantly to the understanding of this neuronal loss. Ultrastructural examination revealed characteristics of apoptosis and autophagic degeneration in melanized neurons of the substantia nigra in PD patients. The results suggest that even at the final stage of the disease, the dopaminergic neurons are undergoing active process of cell death.

Parkinson’s Disease and Related Disorders, 2006

An abnormally frequent atypical levodopa-unresponsive, akinetic-rigid syndrome with some similari... more An abnormally frequent atypical levodopa-unresponsive, akinetic-rigid syndrome with some similarity to PSP was identified in the Caribbean island Guadeloupe, and was associated with the consumption of plants of the Annonacea family, especially Annona muricata (corossol, soursop) suggesting a possible toxic etiology. Annonaceae contain two groups of potential toxins, alkaloids and acetogenins. Both alkaloids and annonacin, the most abundant acetogenin, were toxic in vitro to dopaminergic and other neurons. However we have focused our work on annonacin for two reasons: (1) annonacin was toxic in nanomolar concentrations, whereas micromolar concentrations of the alkaloids were needed, (2) acetogenins are potent mitochondrial poisons, like other parkinsonism-inducing compounds. We have also shown that high concentrations of annonacin are present in the fruit or aqueous extracts of the leaves of A. muricata, can cross the blood brain barrier since it was detected in brain parenchyma of rats treated chronically with the molecule, and induced neurodegeneration of basal ganglia in these animals, similar to that observed in atypical parkinsonism. These studies reinforce the concept that consumption of Annonaceae may contribute to the pathogenesis of atypical parkinsonism in Guadeloupe.

The Journal of Neuroscience, 2007

A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated w... more A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated with the consumption of anonaceous plants that contain acetogenins, potent lipophilic inhibitors of complex I of the mitochondrial respiratory chain. To test the hypothesis that annonacin, a prototypical acetogenin, contributes to the etiology of the disease, we investigated whether annonacin affects the cellular distribution of the protein tau. In primary cultures of rat striatal neurons treated for 48 h with annonacin, there was a concentration-dependent decrease in ATP levels, a redistribution of tau from the axons to the cell body, and cell death. Annonacin induced the retrograde transport of mitochondria, some of which had tau attached to their outer membrane. Taxol, a drug that displaces tau from microtubules, prevented the somatic redistribution of both mitochondria and tau but not cell death. Antioxidants, which scavenged the reactive oxygen species produced by complex I inhibitio...

Proceedings of the National Academy of Sciences, 2000

Caspase-3 is an effector of apoptosis in experimental models of Parkinson's disease (PD). How... more Caspase-3 is an effector of apoptosis in experimental models of Parkinson's disease (PD). However, its potential role in the human pathology remains to be demonstrated. Using caspase-3 immunohistochemistry on the postmortem human brain, we observed a positive correlation between the degree of neuronal loss in dopaminergic (DA) cell groups affected in the mesencephalon of PD patients and the percentage of caspase-3-positive neurons in these cell groups in control subjects and a significant decrease of caspase-3-positive pigmented neurons in the substantia nigra pars compacta of PD patients compared with controls that also could be observed in an animal model of PD. This suggests that neurons expressing caspase-3 are more sensitive to the pathological process than those that do not express the protein. In addition, using an antibody raised against activated caspase-3, the percentage of active caspase-3-positive neurons among DA neurons was significantly higher in PD patients than ...

Molecular Pharmacology, 2005

We evaluated the neuroprotective potential of tachykinin peptides using a model system in which m... more We evaluated the neuroprotective potential of tachykinin peptides using a model system in which mesencephalic dopaminergic (DA) neurons die spontaneously and selectively as they mature. The three native tachykinins, substance P (SP), neurokinin (NK) A and NKB afforded substantial protection against DA cell demise. The selective NK 1 receptor antagonist GR71251 was sufficient in itself to suppress the effect of SP whereas a co-treatment with GR71251 and the NK 3 receptor antagonist SB218795 was required to prevent the effects of both NKA and NKB. Consistent with these results, GR73632, a selective agonist of NK 1 receptors and [pro7]-NKB, a selective agonist of NK 3 receptors, conferred protection to DA neurons whereas GR64349, which activates specifically NK 2 receptors, did not. DA neurons rescued by tachykinins accumulated [ 3 H]-DA efficiently which suggests that they were also totally functional. Neuroprotection by tachykinins was highly selective for DA neurons, rapidly reversed upon treatment withdrawal and reproduced by, but independent of glial cell line-derived neurotrophic factor. Survival promotion by tachykinins was abolished by blocking voltage-gated Na + channels with tetrodotoxin or N-type voltage-gated Ca 2+ channels with ω-conotoxin-MVIIA, which indicates that an increase in neuronal excitability was crucially involved in this effect. Together, these data further support the notion that the survival of mesencephalic DA neurons during development depends largely on excitatory inputs, which may be provided in part by tachykinins.

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders char... more Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregation in vivo, in vitro and in a cell free system using real-time quaking induced conversion (RT-QuiC). Our results show that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found doxycycline induces a cellular redistribution of the aggregates in an animal model ...

Cells

Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contami... more Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contaminates ecosystems in the French Caribbean. Because OCPs are known to increase the risk of Parkinson’s disease (PD), we tested whether chronic low-level intoxication with CLD could reproduce certain key characteristics of Parkinsonism-like neurodegeneration. For that, we used culture systems of mouse midbrain dopamine (DA) neurons and glial cells, together with the nematode C. elegans as an in vivo model organism. We established that CLD kills cultured DA neurons in a concentration- and time-dependent manner while exerting no direct proinflammatory effects on glial cells. DA cell loss was not impacted by the degree of maturation of the culture. The use of fluorogenic probes revealed that CLD neurotoxicity was the consequence of oxidative stress-mediated insults and mitochondrial disturbances. In C. elegans worms, CLD exposure caused a progressive loss of DA neurons associated with locomoto...

bioRxiv, 2020

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The... more Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the different isoforms of tau protein in a dose-dependent manner, remodeling the resultant species. Furthermore, doxycycline interacts with tau microtubule-binding domain preventing its aggregation. In a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.

Doxycycline is a tetracycline commonly used for its antibiotic properties and capacity to treat a... more Doxycycline is a tetracycline commonly used for its antibiotic properties and capacity to treat acne- and rosacea-like skin lesions. It has also recently demonstrated interesting effects against Parkinson's disease pathomechanisms. Notably, doxycycline was reported to limit amyloid-type aggregation of α-synuclein and curtail neurodegeneration-related inflammatory processes. However, the potential therapeutic interest of doxycycline is limited due to its antibiotic activity. The design of novel doxycycline derivatives was undertaken to generate non-antimicrobial doxycycline derivatives with still neuroprotective properties. Specifically, the dimethyl-amino at C4 group was reduced to significantly diminish the antibiotic activity, and several coupling reactions were performed at position C9 of the D ring. Among 18 novel tetracyclines, seven derivatives with reduced antibiotic activity were more efficient than their parent compound in reducing α-synuclein aggregation. Among those, ...

Movement Disorders

BackgroundHigh consumption of Annona muricata fruit has been previously identified as a risk fact... more BackgroundHigh consumption of Annona muricata fruit has been previously identified as a risk factor for atypical parkinsonism in the French Caribbean islands.ObjectiveWe tested whether consumption of Annonaceae products could worsen the clinical phenotype of patients with any form of degenerative parkinsonism.MethodsWe analyzed neurological data from 180 Caribbean parkinsonian patients and specifically looked for dose effects of lifelong, cumulative Annonaceae consumption on cognitive performance. Using unsupervised clustering, we identified one cluster with mild/moderate symptoms (N = 102) and one with severe symptoms including cognitive impairment (N = 78).ResultsWe showed that even low cumulative consumption of fruits/juices (>0.2 fruit‐years) or any consumption of herbal tea from Annonaceae worsen disease severity and cognitive deficits in degenerative parkinsonism including Parkinson's disease (OR fruits‐juices: 3.76 [95% CI: 1.13–15.18]; OR herbal tea: 2.91 [95% CI: 1.3...

Background: Mechanisms underlying acute brain injury in SARS-CoV-2 patients remain poorly underst... more Background: Mechanisms underlying acute brain injury in SARS-CoV-2 patients remain poorly understood. A better characterization of such mechanisms remains essential to preventing long-term neurological sequelae. Our present aim was to study a panel of biomarkers of neuroinflammation and neurodegeneration in the cerebrospinal fluid (CSF) of NeuroCOVID patients.Methods: We retrospectively collected clinical and CSF biomarkers data from 24 NeuroCOVID adults seen at the University Hospital of Guadeloupe between March and June 2021.Results: Among 24 NeuroCOVID patients, 71% had encephalopathy and 29% a meningoencephalitis. A number of these patients also experienced de novo movement disorder (33%) or stroke (21%). The CSF analysis revealed intrathecal immunoglobulin synthesis in 54% of NeuroCOVID patients (two with a type 2 pattern and 11 with a type 3) and elevated neopterin levels in 75% of them (median 9.1 nM, IQR 5.6-22.1). CSF neurofilament light chain (NfL) was also increased compa...

Cells

To model α-Synuclein (αS) aggregation and neurodegeneration in Parkinson’s disease (PD), we estab... more To model α-Synuclein (αS) aggregation and neurodegeneration in Parkinson’s disease (PD), we established cultures of mouse midbrain dopamine (DA) neurons and chronically exposed them to fibrils 91 (F91) generated from recombinant human αS. We found that F91 have an exquisite propensity to seed the aggregation of endogenous αS in DA neurons when compared to other neurons in midbrain cultures. Until two weeks post-exposure, somal aggregation in DA neurons increased with F91 concentrations (0.01–0.75 μM) and the time elapsed since the initiation of seeding, with, however, no evidence of DA cell loss within this time interval. Neither toxin-induced mitochondrial deficits nor genetically induced loss of mitochondrial quality control mechanisms promoted F91-mediated αS aggregation or neurodegeneration under these conditions. Yet, a significant loss of DA neurons (~30%) was detectable three weeks after exposure to F91 (0.5 μM), i.e., at a time point where somal aggregation reached a plateau...

Tetracyclines have recently emerged as possible therapeutic agents for several diseases of the ce... more Tetracyclines have recently emerged as possible therapeutic agents for several diseases of the central nervous system. Chemically modified tetracycline 3 (also known as Incyclinide, CMT-3 or COL-3), a tetracycline derivative without antibiotic activity that crosses the blood-brain barrier, has been recently validated as a potent anti-inflammatory molecule. The present study discloses a possible mechanism through which COL-3 induces an anti-inflammatory response in cultured microglial cells activated by two different inflammogens: the standard bacterial component lipopolysaccharide (LPS) and the amyloid fibrils of the synaptic protein α-Synuclein (αSa). Under LPS and αSa treatment, COL-3 effectively reduced the production of prototypical

Scientific Reports, 2020

Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote s... more Heparan sulfate (HS) chains, covalently linked to heparan sulfate proteoglycans (HSPG), promote synaptic development and functions by connecting various synaptic adhesion proteins (AP). HS binding to AP could vary according to modifications of HS chains by different sulfotransferases. 3-O-sulfotransferases (Hs3sts) produce rare 3-O-sulfated HSs (3S-HSs), of poorly known functions in the nervous system. Here, we showed that a peptide known to block herpes simplex virus by interfering with 3S-HSs in vitro and in vivo (i.e. G2 peptide), specifically inhibited neural activity, reduced evoked glutamate release, and impaired synaptic assembly in hippocampal cell cultures. A role for 3S-HSs in promoting synaptic assembly and neural activity is consistent with the synaptic interactome of G2 peptide, and with the detection of Hs3sts and their products in synapses of cultured neurons and in synaptosomes prepared from developing brains. Our study suggests that 3S-HSs acting as receptors for he...

Molecular Pharmacology, 2018

European Respiratory Journal, 2019

Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading... more Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (https://clinicaltrials.gov;NCT01583088). Myofibre type, size and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed using multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity (VC), maximal inspiratory pressure, sniff nasal inspiratory pressure (SNIP) and twitch transdiaphragma...

Neuron, May 18, 2016

Parkinson disease (PD) is a multifactorial neurodegenerative disorder, the etiology of which rema... more Parkinson disease (PD) is a multifactorial neurodegenerative disorder, the etiology of which remains largely unknown. Progressive impairment of voluntary motor control, which represents the primary clinical feature of the disease, is caused by a loss of midbrain substantia nigra dopamine (DA) neurons. We present here a synthetic overview of cell-autonomous mechanisms that are likely to participate in DA cell death in both sporadic and inherited forms of the disease. In particular, we describe how damage to vulnerable DA neurons may arise from cellular disturbances produced by protein misfolding and aggregation, disruption of autophagic catabolism, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, or loss of calcium homeostasis. Where pertinent, we show how these mechanisms may mutually cooperate to promote neuronal death.

Human Molecular Genetics, 2016

Mutations in PARK2, encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autoso... more Mutations in PARK2, encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autosomal recessive Parkinson's disease (PD). Loss of PARK2 function compromises mitochondrial quality by affecting mitochondrial biogenesis, bioenergetics, dynamics, transport and turnover. We investigated the impact of PARK2 dysfunction on the endoplasmic reticulum (ER)-mitochondria interface, which mediates Ca 2+ exchange between the two compartments and is essential for Parkindependent mitophagy. Confocal and electron microscopy analyses showed the ER and mitochondria to be in closer proximity in primary fibroblasts from PARK2 KO mice and PD patients with PARK2 mutations than in controls. Ca 2+ flux to the cytosol was also modified, due to enhanced ER-tomitochondria Ca 2+ transfers, a change that was also observed in neurons derived from induced pluripotent stem cells of a patient with PARK2 mutations. Subcellular fractionation showed the abundance of the Parkin substrate mitofusin 2 (Mfn2), which is known to modulate the ERmitochondria interface, to be specifically higher in the mitochondrion-associated ER membrane compartment in PARK2 KO tissue. Mfn2 downregulation or the exogenous expression of normal Parkin restored cytosolic Ca 2+ transients in fibroblasts from patients with PARK2 mutations. By contrast, a catalytically inactive PD-related Parkin variant had no effect. Overall, our data suggest that Parkin is directly involved in regulating ER-mitochondria contacts and provide new insight into the role of the loss of Parkin function in PD development.

Histology and histopathology, 1997

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive cell lo... more Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive cell loss confined mostly to dopaminergic neurons of the substantia nigra. Several factors, including oxidative stress, and decreased activity of complex I mitochondrial respiratory chain, are involved in the degenerative process. Yet, the underlying mechanisms leading to dopaminergic cell loss remain elusive. Morphological assessment for different modes of cell death: apoptosis, necrosis or autophagic degeneration, can contribute significantly to the understanding of this neuronal loss. Ultrastructural examination revealed characteristics of apoptosis and autophagic degeneration in melanized neurons of the substantia nigra in PD patients. The results suggest that even at the final stage of the disease, the dopaminergic neurons are undergoing active process of cell death.

Parkinson’s Disease and Related Disorders, 2006

An abnormally frequent atypical levodopa-unresponsive, akinetic-rigid syndrome with some similari... more An abnormally frequent atypical levodopa-unresponsive, akinetic-rigid syndrome with some similarity to PSP was identified in the Caribbean island Guadeloupe, and was associated with the consumption of plants of the Annonacea family, especially Annona muricata (corossol, soursop) suggesting a possible toxic etiology. Annonaceae contain two groups of potential toxins, alkaloids and acetogenins. Both alkaloids and annonacin, the most abundant acetogenin, were toxic in vitro to dopaminergic and other neurons. However we have focused our work on annonacin for two reasons: (1) annonacin was toxic in nanomolar concentrations, whereas micromolar concentrations of the alkaloids were needed, (2) acetogenins are potent mitochondrial poisons, like other parkinsonism-inducing compounds. We have also shown that high concentrations of annonacin are present in the fruit or aqueous extracts of the leaves of A. muricata, can cross the blood brain barrier since it was detected in brain parenchyma of rats treated chronically with the molecule, and induced neurodegeneration of basal ganglia in these animals, similar to that observed in atypical parkinsonism. These studies reinforce the concept that consumption of Annonaceae may contribute to the pathogenesis of atypical parkinsonism in Guadeloupe.

The Journal of Neuroscience, 2007

A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated w... more A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated with the consumption of anonaceous plants that contain acetogenins, potent lipophilic inhibitors of complex I of the mitochondrial respiratory chain. To test the hypothesis that annonacin, a prototypical acetogenin, contributes to the etiology of the disease, we investigated whether annonacin affects the cellular distribution of the protein tau. In primary cultures of rat striatal neurons treated for 48 h with annonacin, there was a concentration-dependent decrease in ATP levels, a redistribution of tau from the axons to the cell body, and cell death. Annonacin induced the retrograde transport of mitochondria, some of which had tau attached to their outer membrane. Taxol, a drug that displaces tau from microtubules, prevented the somatic redistribution of both mitochondria and tau but not cell death. Antioxidants, which scavenged the reactive oxygen species produced by complex I inhibitio...

Proceedings of the National Academy of Sciences, 2000

Caspase-3 is an effector of apoptosis in experimental models of Parkinson's disease (PD). How... more Caspase-3 is an effector of apoptosis in experimental models of Parkinson's disease (PD). However, its potential role in the human pathology remains to be demonstrated. Using caspase-3 immunohistochemistry on the postmortem human brain, we observed a positive correlation between the degree of neuronal loss in dopaminergic (DA) cell groups affected in the mesencephalon of PD patients and the percentage of caspase-3-positive neurons in these cell groups in control subjects and a significant decrease of caspase-3-positive pigmented neurons in the substantia nigra pars compacta of PD patients compared with controls that also could be observed in an animal model of PD. This suggests that neurons expressing caspase-3 are more sensitive to the pathological process than those that do not express the protein. In addition, using an antibody raised against activated caspase-3, the percentage of active caspase-3-positive neurons among DA neurons was significantly higher in PD patients than ...

Molecular Pharmacology, 2005

We evaluated the neuroprotective potential of tachykinin peptides using a model system in which m... more We evaluated the neuroprotective potential of tachykinin peptides using a model system in which mesencephalic dopaminergic (DA) neurons die spontaneously and selectively as they mature. The three native tachykinins, substance P (SP), neurokinin (NK) A and NKB afforded substantial protection against DA cell demise. The selective NK 1 receptor antagonist GR71251 was sufficient in itself to suppress the effect of SP whereas a co-treatment with GR71251 and the NK 3 receptor antagonist SB218795 was required to prevent the effects of both NKA and NKB. Consistent with these results, GR73632, a selective agonist of NK 1 receptors and [pro7]-NKB, a selective agonist of NK 3 receptors, conferred protection to DA neurons whereas GR64349, which activates specifically NK 2 receptors, did not. DA neurons rescued by tachykinins accumulated [ 3 H]-DA efficiently which suggests that they were also totally functional. Neuroprotection by tachykinins was highly selective for DA neurons, rapidly reversed upon treatment withdrawal and reproduced by, but independent of glial cell line-derived neurotrophic factor. Survival promotion by tachykinins was abolished by blocking voltage-gated Na + channels with tetrodotoxin or N-type voltage-gated Ca 2+ channels with ω-conotoxin-MVIIA, which indicates that an increase in neuronal excitability was crucially involved in this effect. Together, these data further support the notion that the survival of mesencephalic DA neurons during development depends largely on excitatory inputs, which may be provided in part by tachykinins.

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders char... more Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregation in vivo, in vitro and in a cell free system using real-time quaking induced conversion (RT-QuiC). Our results show that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found doxycycline induces a cellular redistribution of the aggregates in an animal model ...

Cells

Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contami... more Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contaminates ecosystems in the French Caribbean. Because OCPs are known to increase the risk of Parkinson’s disease (PD), we tested whether chronic low-level intoxication with CLD could reproduce certain key characteristics of Parkinsonism-like neurodegeneration. For that, we used culture systems of mouse midbrain dopamine (DA) neurons and glial cells, together with the nematode C. elegans as an in vivo model organism. We established that CLD kills cultured DA neurons in a concentration- and time-dependent manner while exerting no direct proinflammatory effects on glial cells. DA cell loss was not impacted by the degree of maturation of the culture. The use of fluorogenic probes revealed that CLD neurotoxicity was the consequence of oxidative stress-mediated insults and mitochondrial disturbances. In C. elegans worms, CLD exposure caused a progressive loss of DA neurons associated with locomoto...

bioRxiv, 2020

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The... more Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the different isoforms of tau protein in a dose-dependent manner, remodeling the resultant species. Furthermore, doxycycline interacts with tau microtubule-binding domain preventing its aggregation. In a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.