Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease

Matthew Taylor, Dario Alessi (Lead / Corresponding author)

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Abstract

Autosomal dominant missense mutations that hyperactivate the leucine-rich repeat protein kinase-2 (LRRK2) are a common cause of inherited Parkinson's disease and therapeutic efficacy of LRRK2 inhibitors is being tested in clinical trials. In this review, we discuss the nuts and bolts of our current understanding of how the LRRK2 is misregulated by mutations and how pathway activity is affected by LRRK2 binding to membrane, microtubule filaments, and 14-3-3, as well as by upstream components such as Rab29 and VPS35. We discuss recent work that points toward a subset of Rab proteins comprising key physiological substrates that bind new sets of effectors, such as RILPL1/2, JIP3 and JIP4 after phosphorylation by LRRK2. We explore what is known about how LRRK2 regulates ciliogenesis, the endosomal–lysosomal system, immune responses and interplay with alpha-synuclein and tau and how this might be linked to Parkinson's' disease.
Original languageEnglish
Pages (from-to)102-113
Number of pages12
JournalCurrent Opinion in Cell Biology
Volume63
Early online date7 Feb 2020
DOIs
Publication statusE-pub ahead of print - 7 Feb 2020

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Protein Kinases
Parkinson Disease
alpha-Synuclein
Missense Mutation
Protein Kinase Inhibitors
Microtubules
leucine-rich repeat proteins
Immune System
Phosphorylation
Clinical Trials
Mutation
Membranes
Proteins

Keywords

  • Ciliogenesis
  • Lysosomal stress
  • Neuroinflammation
  • Protein kinase
  • RILPL1
  • Rab GTPase
  • Signal transduction

Cite this

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abstract = "Autosomal dominant missense mutations that hyperactivate the leucine-rich repeat protein kinase-2 (LRRK2) are a common cause of inherited Parkinson's disease and therapeutic efficacy of LRRK2 inhibitors is being tested in clinical trials. In this review, we discuss the nuts and bolts of our current understanding of how the LRRK2 is misregulated by mutations and how pathway activity is affected by LRRK2 binding to membrane, microtubule filaments, and 14-3-3, as well as by upstream components such as Rab29 and VPS35. We discuss recent work that points toward a subset of Rab proteins comprising key physiological substrates that bind new sets of effectors, such as RILPL1/2, JIP3 and JIP4 after phosphorylation by LRRK2. We explore what is known about how LRRK2 regulates ciliogenesis, the endosomal–lysosomal system, immune responses and interplay with alpha-synuclein and tau and how this might be linked to Parkinson's' disease.",
keywords = "Ciliogenesis, Lysosomal stress, Neuroinflammation, Protein kinase, RILPL1, Rab GTPase, Signal transduction",
author = "Matthew Taylor and Dario Alessi",
note = "Work in DRA laboratory on LRRK2 is supported by the Michael J. Fox Foundation for Parkinson's Research [grant numbers 17298 & 6986] and the UK Medical Research Council [grant number MC_UU_12016/2]; the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (Boehringer-Ingelheim, Germany, GlaxoSmithKline, Merck KGaA to D.R.A.). M.T is supported by a PhD Studentship that is cofunded by the UK Medical Research Council and GlaxoSmithKline.",
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AU - Alessi, Dario

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