Ade novocompound targeting α-synuclein improves deficits in models of Parkinson’s disease (original) (raw)
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A de novo compound targeting α-synuclein improves deficits in models of Parkinson's disease
Brain : a journal of neurology, 2016
Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-depend...
Scientific reports, 2018
Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) ...
eBioMedicine, 2020
Background: Progressive neuronal death in monoaminergic nuclei and widespread accumulation of a-synuclein are neuropathological hallmarks of Parkinson's disease (PD). Given that a-synuclein may be an early mediator of the pathological cascade that ultimately leads to neurodegeneration, decreased a-synuclein synthesis will abate neurotoxicity if delivered to the key affected neurons. Methods: We used a non-viral gene therapy based on a new indatraline-conjugated antisense oligonucleotide (IND-ASO) to disrupt the a-synuclein mRNA transcription selectively in monoamine neurons of a PD-like mouse model and elderly nonhuman primates. Molecular, cell biology, histological, neurochemical and behavioral assays were performed. Findings: Intracerebroventricular and intranasal IND-ASO administration for four weeks in a mouse model with AAV-mediated wild-type human a-synuclein overexpression in dopamine neurons prevented the synthesis and accumulation of a-synuclein in the connected brain regions, improving dopamine neurotransmission. Likewise, the four-week IND-ASO treatment led to decreased levels of endogenous a-synuclein protein in the midbrain monoamine nuclei of nonhuman primates, which are affected early in PD. Conclusions: : The inhibition of a-synuclein production in dopamine neurons and its accumulation in cortical/ striatal projection areas may alleviate the early deficits of dopamine function, showing the high translational value of antisense oligonucleotides as a disease modifying therapy for PD and related synucleinopathies.
2021
With the aging of the population, Parkinson’s disease poses a serious socio-economic problem; there is no effective therapy that can arrest/revert the progression of the disease. The hallmarks of Parkinson’s disease and other synucleinopathies are the disordered alpha-synuclein and TPPP/p25. These proteins have neomorphic moonlighting characteristics by displaying both physiological and pathological functions. Physiologically TPPP/p25 regulates the dynamics/stability of the microtubules and is crucial for oligodendrocyte differentiation; while alpha-synuclein is involved in neuronal plasticity modulation and synaptic vesicle pool maintenance. In healthy brain, alpha-synuclein and TPPP/p25 occur predominantly in neurons and oligodendrocytes, respectively; however, they are co-enriched and co-localized in both cell types in brain inclusions in the cases of Parkinson’s disease and multiple system atrophy, respectively. The pathomechanisms of these diseases are largely unknown; the fata...
F1000 - Post-publication peer review of the biomedical literature, 2014
Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.
Annals of the New York Academy of Sciences, 2006
The 15-20 kDa synuclein (SYN) phosphoproteins are abundantly expressed in nervous tissue. Members of the family include ␣and -SYN, and the more distantly related ␥-SYN and synoretin. SYN genes have been identified in Torpedo, canary, and several mammalian species, indicating an evolutionary conserved role. Expression of ␣-SYN was found to be modulated in situations of neuronal remodeling, namely, songbird learning and after target ablation of dopaminergic striatonigral neurons in the rat. The presynaptic localization of ␣-SYN is further supportive of a direct physiological role in neuronal plasticity. The extensive synaptic co-localization of ␣and -SYN might indicate functional redundancy of these highly homologous synucleins. However, ␣-SYN was the only family member identified in Lewy bodies and cytoplasmic inclusions characteristic for multiple system atrophy. Moreover, ␣-SYN was genetically linked to familial Parkinson's disease. The two Parkinson's disease-associated mutations accelerated the intrinsic aggregation property of ␣-SYN in vitro. Post-translational modifications, such as phosphorylation and proteolysis, and/or interaction with other proteins, might regulate ␣-SYN fibril formation in vivo. Cytoskeletal elements and signal transduction intermediates have been recently identified as binding partners for ␣-SYN. Preliminary data available from transgenic mice suggest that (over)expressed human ␣-SYN proteins are less efficiently cleared from the neuronal cytosol. Thus, Parkinson's disease-associated mutations might perturb axonal transport, leading to somal accumulation of ␣-SYN and eventually Lewy body formation.
Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson's disease
Scientific reports, 2017
Evidence suggests that synapses are affected first in Parkinson's disease (PD). Here, we tested the claim that pathological accumulation of α-synuclein, and subsequent synaptic disruption, occur in absence of dopaminergic neuron loss in PD. We determined early synaptic changes in rats that overexpress human α-synuclein by local injection of viral-vectors in midbrain. We aimed to achieve α-synuclein levels sufficient to induce terminal pathology without significant loss of nigral neurons. We tested synaptic disruption in vivo by analyzing motor defects and binding of a positron emission tomography (PET) radioligand to the vesicular monoamine transporter 2, (VMAT2), [(11)C]dihydrotetrabenazine (DTBZ). Animals overexpressing α-synuclein had progressive motor impairment and, 12 weeks post-surgery, showed asymmetric in vivo striatal DTBZ binding. The PET images matched ligand binding in post-mortem tissue, and histological markers of dopaminergic integrity. Histology confirmed the ab...
FEBS Letters
With the aging of population, neurological disorders, and especially disorders involving defects in protein conformation (also known as proteopathies) pose a serious socioeconomic problem. So far there is no effective treatment for most proteopathies, including Parkinson's disease (PD). The mechanism underlying PD pathogenesis is largely unknown, and the hallmark proteins, a-synuclein (SYN) and tubulin polymerization promoting protein (TPPP/p25) are challenging drug targets. These proteins are intrinsically disordered with high conformational plasticity, and have diverse physiological and pathological functions. In the healthy brain, SYN and TPPP/p25 occur in neurons and oligodendrocytes, respectively; however, in PD and multiple system atrophy, they are co-enriched and co-localized in both cell types, thereby marking pathogenesis. Although large inclusions appear at a late disease stage, small, soluble assemblies of SYN promoted by TPPP/p25 are pathogenic. In the light of these issues, we established a new innovative strategy for the validation of a specific drug target based upon the identification of contact surfaces of the pathological SYN-TPPP/p25 complex that may lead to the development of peptidomimetic foldamers suitable for pharmaceutical intervention.