A53T-α-synuclein overexpression in murine locus coeruleus induces Parkinson’s disease-like pathology in neurons and glia

Acta Neuropathologica Communications

Lars Timmermann¹  Martin Timo Henrich¹  Fanni Fruzsina Geibl¹  Wei-Hua Chiu¹  Bolam Lee¹  Lina Anita Matschke¹  Wolfgang Hermann Oertel¹  Niels Decher²  Jonathan Michael Brotchie³  James Benjamin Koprich³ 

[1] Department of Neurology, Philipps University Marburg;Department of Physiology and Pathophysiology, Philipps University Marburg;Krembil Research Institute, Toronto Western Hospital, University Health Network;

关键词: Parkinson’s disease;    Locus coeruleus;    Alpha-synuclein;    Adeno-associated viral vectors;    Prodromal mouse model;    Microglia, noradrenergic neurons;   

DOI  :  10.1186/s40478-018-0541-1

来源: DOAJ

【 摘 要 】

Abstract Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase of Parkinson’s disease and contributes to a variety of non-motor symptoms, e.g. depression, anxiety and REM sleep behavior disorder. This study was designed to establish the first locus coeruleus α-synucleinopathy mouse model, which should provide sufficient information about the time-course of noradrenergic neurodegeneration, replicate cardinal histopathological features of the human Parkinson’s disease neuropathology and finally lead to robust histological markers, which are sufficient to assess the pathological changes in a quantitative and qualitative way. We show that targeted viral vector-mediated overexpression of human mutant A53T-α-synuclein in vivo in locus coeruleus neurons of wild-type mice resulted in progressive noradrenergic neurodegeneration over a time frame of 9 weeks. Observed neuronal cell loss was accompanied by progressive α-synuclein phosphorylation, formation of proteinase K-resistant α-synuclein-aggregates, accumulation of Ubi-1- and p62-positive inclusions in microglia and induction of progressive micro- and astrogliosis. Apart from this local pathology, abundant α-synuclein-positive axons were found in locus coeruleus output regions, indicating rapid anterograde axonal transport of A53T-α-synuclein. Taken together, we present the first model of α-synucleinopathy in the murine locus coeruleus, replicating essential morphological features of human Parkinson’s disease pathology. This new model may contribute to the research on prodromal Parkinson’s disease, in respect to pathophysiology and the development of disease-modifying therapy.

【 授权许可】

Unknown