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Publication Detail
A role for the Parkinson's disease kinase LRRK2 in endo-lysosomal and cytoskeletal function
  • Publication Type:
    Thesis/Dissertation
  • Authors:
    Pellegrini L
  • Date awarded:
    2018
  • Pagination:
    1, 267
  • Status:
    Unpublished
  • Awarding institution:
    UCL (University College London)
  • Language:
    English
  • Date Submitted:
    14/12/2017
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of people globally. Like other age-related conditions, inheritance of genetic variations contributes to PD pathogenesis. Mutations in leucine-rich repeat kinase 2 (LRRK2) are linked with familial forms of late-onset PD. Importantly, the LRRK2 locus has been identified by genome-wide association studies to contribute to risk of sporadic disease. These observations suggest that the study of LRRK2 cell biological function and dysfunction might shed light on the pathogenesis of PD. LRRK2 is a large multidomain cytosolic protein reported to play a role in a variety of cellular functions such as cytoskeletal dynamics, vesicular trafficking and autophagy. Mouse models deficient of LRRK2 or harbouring the pathogenic human G2019S mutation do not show typical PD brain pathology. However, reported phenotypic kidney pathology in LRRK2 knockout mice provides a rationale to investigate LRRK2 knockout and G2019S knockin kidneys to further elucidate the biological role of LRRK2. Using an unbiased quantitative proteomic approach, significant alterations in protein levels associated with cytoskeletal, lysosomal, vesicular trafficking and control of protein translation were observed in Lrrk2 knockout but not G2019S knockin tissue. Lysosomal protein accumulation and changes in expression of a subset of cytoskeletal proteins were validated using orthogonal techniques in independent cohorts of mice across several age time points. Very few protein changes were observed in brain or varied in opposite directions in knockout versus knockin mice. A role for LRRK2 in the endo-lysosomal pathway was further confirmed in primary kidney cells from LRRK2 knockout mice. Overall, these results imply LRRK2 co-ordinated responses in protein trafficking and cytoskeletal dynamics, and argue against a simple dominant negative role for the G2019S mutation.
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