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

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Abstract

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.

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Abbreviations

aSyn:

Alpha-synuclein

pSyn:

p-Ser129 alpha-synuclein

ASO:

Antisense oligonucleotide

CA:

Cornu ammonis

DG:

Dentate gyrus

DPI:

Days post-injection

DPT:

Days post-transduction

PD:

Parkinson’s disease

DLB:

Dementia with Lewy bodies

PDD:

Parkinson’s disease with dementia

PFF:

Pre-formed fibril

LB/LN:

Lewy body/Lewy neurite

Ms:

Mouse

Hu:

Human

SNpc:

Substantia nigra pars compacta

wt:

Wildtype

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Acknowledgements

We thank Drs. Xiaolu Yang, Michael Henderson, Dustin Covell, Chao Peng, Kurt Brunden, and John Trojanowski for helpful discussions and insights. This research was funded in part by the NIH grants NS088322, NS053488, T32-AG000255, and a pilot grant from University of Pennsylvania Institute for Translational Medicine and Therapeutics. T. C. was an employee of Ionis Pharmaceuticals at the time when data were generated and interpreted. The remaining authors have no additional financial interests.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Philadelphia, PA, 19104-4283, USA

    Esteban Luna, Samantha C. Decker, Dawn M. Riddle, Anna Caputo, Bin Zhang, Virginia M. Y. Lee & Kelvin C. Luk

  2. Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283, USA

    Carrie Caswell & Sharon X. Xie

  3. Ionis Pharmaceuticals, Carlsbad, CA, USA

    Tracy Cole

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  1. Esteban Luna
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  2. Samantha C. Decker
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  5. Bin Zhang
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  9. Virginia M. Y. Lee
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  10. Kelvin C. Luk
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Contributions

Conceptualization, EL and KCL; Methodology, EL, AC, BZ, SCD, DMR, and KCL; Investigation, EL, CC, SX, and KCL; Writing—original draft, EL; Writing—review and editing, EL, VMYL and KCL; Funding Acquisition, KCL, VMYL; Resources, KCL; Supervision, KCL.

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Correspondence to Kelvin C. Luk.

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Luna, E., Decker, S.C., Riddle, D.M. et al. Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity. Acta Neuropathol 135, 855–875 (2018). https://doi.org/10.1007/s00401-018-1829-8

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  • DOI: https://doi.org/10.1007/s00401-018-1829-8

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