generation-alpha-synuclein-preformed-fibrils-from-monomers-use

Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo

Use of the in vivo alpha-synuclein preformed fibril (&#945;-syn PFF) model of synucleinopathy is gaining popularity among researchers aiming to model ...

University of Pennsylvania Perelman School of Medicine

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

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

After publication of the original article [1] it was noted that the name of author, D. Luke Fisher, was erroneously typeset in both the PDF and online formats of the manuscript as Luke D. Fisher.

Correction to: Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration.

The accumulation of intraneuronal inclusions containing misfolded alpha-synuclein (aSyn) within the central nervous system (CNS) is a common feature found in several neurodegenerative disorders including Parkinson's disease (PD). Emerging evidence indicates that aSyn amyloid fibrils, a configuration that is present within these characteristic inclusions, are capable of self-replicating by templating the conversion of endogenously expressed aSyn in neurons. Stereotaxic administration of synthetic α-synuclein preformed fibrils (PFFs) into the mouse brain has been shown to seed the formation of intracellular aSyn pathology reminiscent of Lewy body (LB) inclusions present in human PD and related synucleinopathies. Moreover, pathology can be targeted to specific CNS regions. This experimental approach provides a versatile platform for investigating PD-like LB pathology in vivo. We focus here on procedures for initiating aSyn inclusion formation at various regions of the mouse brain using computer-assisted motorized stereotaxic microinjection of aSyn PFFs and discuss appropriate strategies for controls and analysis.

Article	Year
Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity. Acta neuropathologica\| PubMed ID: 29502200	2018
Correction to: Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. Journal of neuroinflammation\| PubMed ID: 29843738	2018
Stereotaxic Targeting of Alpha-Synuclein Pathology in Mouse Brain Using Preformed Fibrils. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 30771169	2019

Kelvin C. Luk

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