Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation

Author:

Geertsma Haley M12ORCID,Suk Terry R12ORCID,Ricke Konrad M123ORCID,Horsthuis Kyra12,Parmasad Jean-Louis A12ORCID,Fisk Zoe A123ORCID,Callaghan Steve M12ORCID,Rousseaux Maxime W C12345ORCID

Affiliation:

1. Department of Cellular and Molecular Medicine , University of Ottawa, Ottawa, ON K1H8M5 , Canada

2. University of Ottawa Brain and Mind Research Institute , Ottawa, ON K1H8M5 , Canada

3. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD

4. Ottawa Institute of Systems Biology , University of Ottawa, Ottawa, ON K1H8M5 , Canada

5. Eric Poulin Center for Neuromuscular Diseases , University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H8M5 , Canada

Abstract

Abstract A growing body of evidence suggests that nuclear alpha-synuclein (αSyn) plays a role in the pathogenesis of Parkinson’s disease (PD). However, this question has been difficult to address as controlling the localization of αSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. To overcome this, we engineered SncaNLS mice, which localize endogenous αSyn to the nucleus. We characterized these mice on a behavioral, histological and biochemical level to determine whether the increase of nuclear αSyn is sufficient to elicit PD-like phenotypes. SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to αSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, including Darpp32, Pde10a and Gng7, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared with controls. These results suggest that chronic endogenous nuclear αSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of αSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.

Funder

Government of Canada

Basic Research Fellowship from Parkinson Canada

Ontario Graduate Scholarship

Dave and Jill Hogg

Michael J. Fox Foundation for Parkinson’s Research/Aligning Science Across Parkinson’s Initiative–Collaborative Research Network

Canadian Institutes of Health Research

Parkinson’s Foundation Stanley Fahn Junior Faculty Award

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3