Intracellular A53T Mutant α-Synuclein Impairs Adult Hippocampal Newborn Neuron Integration.

Martin Regensburger,Judith Stemick,Eliezer Masliah,Zacharias Kohl,Beate Winner

doi:10.3389/fcell.2020.561963

Abstract

Dendritic dysfunction is an early event in α-synuclein (α-syn) mediated neurodegeneration. Altered postsynaptic potential and loss of dendritic spines have been observed in different in vitro and in vivo models of synucleinopathies. The integration of newborn neurons into the hippocampus offers the possibility to study dendrite and spine formation in an adult environment. Specifically, survival of hippocampal adult newborn neurons is regulated by synaptic input and was reduced in a mouse model transgenic for human A53T mutant α-syn. We thus hypothesized that dendritic integration of newborn neurons is impaired in the adult hippocampus of A53T mice. We analyzed dendritic morphology of adult hippocampal neurons 1 month after retroviral labeling. Dendrite length was unchanged in the dentate gyrus of A53T transgenic mice. However, spine density and mushroom spine density of newborn neurons were severely decreased. In this mouse model, transgenic α-syn was expressed both within newborn neurons and within their environment. To specifically determine the cell autonomous effects, we analyzed cell-intrinsic overexpression of A53T α-syn using a retrovirus. Since A53T α-syn overexpressing newborn neurons exhibited decreased spine density 1 month after labeling, we conclude that cell-intrinsic A53T α-syn impairs postsynaptic integration of adult hippocampal newborn neurons. Our findings further support the role of postsynaptic degeneration as an early feature in synucleinopathies and provide a model system to study underlying mechanisms.

Highlights

Accumulation of α-synuclein (α-syn) is the neuropathological hallmark of synucleinophathies like Parkinson’s disease (PD), resulting in cytoplasmic inclusions called Lewy bodies (Spillantini et al, 1997; Goedert et al, 2012)
It was previously shown that at the age of 4 months, proliferation and survival of newborn neurons are impaired in A53T-tg mice (Kohl et al, 2012)
Using an antibody specific for human α-syn, we found that transgenic A53T α-syn was widely expressed in the dentate gyrus, including GFP positive newborn neurons (Figure 1A)

Summary

Introduction

Accumulation of α-synuclein (α-syn) is the neuropathological hallmark of synucleinophathies like Parkinson’s disease (PD), resulting in cytoplasmic inclusions called Lewy bodies (Spillantini et al, 1997; Goedert et al, 2012). The A53T α-syn mutation causes early-onset familial PD (Polymeropoulos et al, 1996). The A53T mutation increases levels of oligomeric α-syn species (Conway et al, 2000a; Winner et al, 2011a; Zambon et al, 2019). In A53T-linked familial PD, non-motor symptoms including cognitive impairment were reported (Puschmann et al, 2009). Post-mortem analyses of A53T PD cases revealed widespread accumulation of insoluble α-syn, including the hippocampus (Duda et al, 2002; Kotzbauer et al, 2004)

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Conclusion