Regulation of physiologic actions of LRRK2: Focus on autophagy

Andrew Ferree, Maria Guillily, Hu Li, Katelyn Smith, Aki Takashima, Rachel Squillace, Manfred Weigele, James J. Collins, Benjamin Wolozin

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. Objectives: To investigate mechanisms by which LRRK2 might cause PD. Methods: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. Results: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. Conclusion: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.

Original languageEnglish (US)
Pages (from-to)238-241
Number of pages4
JournalNeurodegenerative Diseases
Volume10
Issue number1-4
DOIs
StatePublished - Apr 2012
Externally publishedYes

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Keywords

  • Autophagy
  • Familial and sporadic Parkinson's disease
  • LRRK2 mutations

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Ferree, A., Guillily, M., Li, H., Smith, K., Takashima, A., Squillace, R., Weigele, M., Collins, J. J., & Wolozin, B. (2012). Regulation of physiologic actions of LRRK2: Focus on autophagy. Neurodegenerative Diseases, 10(1-4), 238-241. https://doi.org/10.1159/000332599