LRRK2 activity does not dramatically alter α-synuclein pathology in primary neurons

Acta Neuropathologica Communications

Michael X. Henderson¹  Chao Peng¹  John Q. Trojanowski¹  Virginia M. Y. Lee¹ 

[1] Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine;

关键词: LRRK2;    Synuclein;    pS129;    Aggregates;    Inhibitor;    G2019S;   

DOI  :  10.1186/s40478-018-0550-0

来源: DOAJ

【 摘 要 】

Abstract Mutations in leucine-rich repeat kinase (LRRK2) are the most common cause of heritable Parkinson’s disease (PD), and the most common mutations in LRRK2 lead to elevated kinase activity. For these reasons, inhibitors targeting LRRK2 have been the subject of intense research and development. However, it has been difficult to develop preclinical models that recapitulate PD-relevant LRRK2 phenotypes. The primary pathology in PD is the Lewy body (LB), which is a cytoplasmic aggregate of α-synuclein. The recent demonstration that LB-like aggregates of α-synuclein can be induced in primary neurons has provided a robust model for testing genetic modifiers of PD-relevant aggregation and neurodegeneration. In this study, we test the modulation of α-synuclein pathology by LRRK2 in primary neuron cultures using biochemistry and immunocytochemistry. We find that expression of familial mutant G2019S LRRK2 does not dramatically elevate the pathological burden of α-synuclein or neurodegeneration in neurons. We further test three LRRK2 inhibitors in two strains of wildtype neurons and find that even robust LRRK2 inhibition is insufficient to reduce α-synuclein pathology. LRRK2 inhibitors similarly had no effect in neurons with α-synuclein pathology seeded by human brain-derived pathological α-synuclein. Finally, we find that this lack of pathological modulation by LRRK2 was not confined to hippocampal neurons, but was also absent in midbrain dopaminergic neuron cultures. These data demonstrate that LRRK2 activity does not have more than minor effects on α-synuclein pathology in primary neurons, and more complex models may be needed to evaluate the ability of LRRK2 inhibitors to treat PD.

【 授权许可】

Unknown