Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons

NEUROBIOLOGY OF DISEASE

卷:111

Article

Schapansky, Jason¹  Khasnavis, Saurabh¹  DeAndrade, Mark P.¹  Nardozzi, Jonathan D.¹  Falkson, Samuel R.¹  Boyd, Justin D.¹  Sanderson, John B.¹  Bartels, Tim¹  Melrose, Heather L.²  LaVoie, Matthew J.¹ 

[1] Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

[2] Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA

关键词: LRRK2;    alpha-Synuclein;    Tau;    Tau phosphorylation;    Lysosome;    Parkinson's disease;   

DOI  :  10.1016/j.nbd.2017.12.005

来源: Elsevier

【 摘 要 】

Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble alpha-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of alpha-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble alpha-synuclein and increased neuronal release of alpha-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and alpha-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal alpha-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD.

【 授权许可】

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