Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo
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ORIGINAL PAPER
Neuronal activity modulates alpha‑synuclein aggregation and spreading in organotypic brain slice cultures and in vivo Qihui Wu1 · Muhammad A. Shaikh1 · Emily S. Meymand1 · Bin Zhang1 · Kelvin C. Luk1 · John Q. Trojanowski1 · Virginia M.‑Y. Lee1 Received: 24 August 2020 / Revised: 15 September 2020 / Accepted: 16 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Alpha-synuclein (αSyn) preformed fibrils (PFF) induce endogenous αSyn aggregation leading to reduced synaptic transmission. Neuronal activity modulates release of αSyn; however, whether neuronal activity regulates the spreading of αSyn pathology remains elusive. Here, we established a hippocampal slice culture system from wild-type (WT) mice and found that both Ca2+ influx and the uptake of αSyn PFF were higher in the CA3 than in the CA1 sub-region. Pharmacologically enhancing neuronal activity substantially increased αSyn pathology in αSyn PFF-treated hippocampal or midbrain slice cultures and accelerated dopaminergic neuron degeneration. Consistently, neuronal hyperactivity promoted PFF trafficking along axons/dendrites within microfluidic chambers. Unexpectedly, enhancing neuronal activity in LRRK2 G2019S mutant slice cultures further increased αSyn pathology, especially with more Lewy body (LB) forming than in WT slice cultures. Finally, following injection of αSyn PFF and chemogenetic modulators into the dorsal striatum of WT mice, both motor behavior and αSyn pathology were exacerbated likely by enhancing neuronal activity, since they were ameliorated by reducing neuronal activity. Thus, a greater understanding of the impact of neuronal activity on αSyn aggregation and spreading, as well as dopaminergic neuronal vulnerability, may provide new therapeutic strategies for patients with LB disease (LBD). Keywords Organotypic brain slice culture · Neuronal activity · Alpha-synuclein aggregation · Parkinson’s disease
Introduction Misfolded alpha-synuclein (αSyn) forms neuronal inclusions known as Lewy bodies (LB) and Lewy neurites (LN), which are the pathological hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), while glial cytoplasmic inclusions (GCI) in multiple system atrophy (MSA) also contain fibrillar αSyn, but are found in oligodendroglia rather than in neurons [52, 53]. αSyn pathology is also commonly abundant in the brains of Alzheimer’s disease (AD)
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02227-6) contains supplementary material, which is available to authorized users. * Virginia M.‑Y. Lee [email protected] 1
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104‑4283, USA
patients [28], and neurodegenerative diseases with αSyn pathology are commonly referred to as synucleinopathies. PD is predominantly recognized for its motor symptoms (tremor, rigidity,
