The Michael J. Fox Foundation's Strategies for Accelerating Translation of LRRK2 into Therapies for Parkinson Disease.
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ABSTRACT:
SUBMITTER: Padmanabhan S
PROVIDER: S-EPMC7466022 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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The Michael J. Fox Foundation's Strategies for Accelerating Translation of LRRK2 into Therapies for Parkinson Disease.
Padmanabhan Shalini S Fiske Brian K BK Baptista Marco A S MAS
Cells 20200811 8
Since 2005, The Michael J. Fox Foundation for Parkinson's Research (MJFF) has invested significant funding and non-funding effort to accelerate research and drug development activity around the Parkinson disease (PD)-associated protein LRRK2. MJFF has spearheaded multiple public/private pre-competitive collaborations that have contributed to our understanding of LRRK2 function; de-risked potential safety questions around the therapeutic use of LRRK2 kinase inhibitors; and generated critical rese ...[more]
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Project description:Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic causes of Parkinson disease (PD) and genome-wide association studies identify LRRK2 sequence variants as risk factors for sporadic PD. Intact kinase function appears critical for the toxicity of LRRK2 PD mutants, yet our understanding of how LRRK2 causes neurodegeneration remains limited. We find that most LRRK2 PD mutants abnormally enhance LRRK2 oligomerization, causing it to form filamentous structures in transfections of cell lines or primary neuronal cultures. Strikingly, ultrastructural analyses, including immuno-electron microscopy and electron microscopic tomography, demonstrate that these filaments consist of LRRK2 recruited onto part of the cellular microtubule network in a well-ordered, periodic fashion. Like LRRK2-related neurodegeneration, microtubule association requires intact kinase function and the WD40 domain, potentially linking microtubule binding and neurodegeneration. Our observations identify a novel effect of LRRK2 PD mutations and highlight a potential role for microtubules in the pathogenesis of LRRK2-related neurodegeneration.
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