Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity

作者: Esteban Luna , Samantha C. Decker , Dawn M. Riddle , Anna Caputo , Bin Zhang

DOI: 10.1007/S00401-018-1829-8

关键词:

摘要: The accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson's disease (PD) dementia with Lewy bodies (DLB). However, the precise relationship between pathology neurotoxicity why these processes disproportionately affect certain subpopulations are poorly understood. We show here that Math2-expressing neurons in hippocampal Cornu ammonis (CA), a region significantly affected by aSyn advanced PD DLB, highly susceptible to pathological seeding pre-formed fibrils (PFFs), contrast dentate gyrus neurons, which relatively spared. Math2+ also exhibited more rapid severe cell both vitro vivo models synucleinopathy. Toxicity resulting from PFF exposure was dependent on endogenous could be attenuated N-acetyl-cysteine through glutathione-dependent process. Moreover, expression levels strongly correlate relative vulnerability among subtypes contained highest amount. Consistent this, antisense oligonucleotide (ASO)-mediated knockdown reduced neuronal time-dependent manner. significant neuroprotection observed only early ASO intervention substantial reduction pathology, indicating toxicity occurs after critical threshold burden is exceeded vulnerable neurons. Together, our findings reveal considerable heterogeneity suggest this may contribute selective context synucleinopathies.

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