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A de novo compound targeting α-synuclein improves deficits in models of Parkinson's disease
- Source :
- Brain : a journal of neurology, vol 139, iss Pt 12
- Publication Year :
- 2016
- Publisher :
- eScholarship, University of California, 2016.
-
Abstract
- 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-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and other synucleinopathies.
- Subjects :
- 0301 basic medicine
Aging
Parkinson's disease
animal diseases
alpha-synuclein
experimental models
Neurodegenerative
Medical and Health Sciences
Transgenic
Antiparkinson Agents
chemistry.chemical_compound
Mice
0302 clinical medicine
Drug Discovery
Behavior, Animal
Parkinson Disease
Cell biology
5.1 Pharmaceuticals
Neurological
alpha-Synuclein
synucleinopathy
Drug
Development of treatments and therapeutic interventions
Genetically modified mouse
Transgene
Mice, Transgenic
Biology
Dose-Response Relationship
03 medical and health sciences
In vivo
mental disorders
medicine
Acquired Cognitive Impairment
Animals
Humans
cellular mechanisms
Alpha-synuclein
Synucleinopathies
Behavior
Neurology & Neurosurgery
Dose-Response Relationship, Drug
Dementia with Lewy bodies
Animal
Psychology and Cognitive Sciences
Neurosciences
medicine.disease
In vitro
nervous system diseases
Brain Disorders
Disease Models, Animal
030104 developmental biology
nervous system
chemistry
Disease Models
Parkinson’s disease
Dementia
Neurology (clinical)
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Brain : a journal of neurology, vol 139, iss Pt 12
- Accession number :
- edsair.doi.dedup.....94e17d784387b62c9ca849ff394fe12f