LRRK2 pathobiology in Parkinson's disease

Ian Martin, Jungwoo Wren Kim, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Mutations in the catalytic Roc-COR and kinase domains of leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD). LRRK2 mutations cause PD with age-related penetrance and clinical features identical to late-onset sporadic PD. Biochemical studies support an increase in LRRK2 kinase activity and a decrease in GTPase activity for kinase domain and Roc-COR mutations, respectively. Strong evidence exists that LRRK2 toxicity is kinase dependent leading to extensive efforts to identify selective and brain-permeable LRRK2 kinase inhibitors for clinical development. Cell and animal models of PD indicate that LRRK2 mutations affect vesicular trafficking, autophagy, protein synthesis, and cytoskeletal function. Although some of these biological functions are affected consistently by most diseaselinked mutations, others are not and it remains currently unclear how mutations that produce variable effects on LRRK2 biochemistry and function all commonly result in the degeneration and death of dopamine neurons. LRRK2 is typically present in Lewy bodies and its toxicity in mammalian models appears to be dependent on the presence of a-synuclein, which is elevated in human iPS-derived dopamine neurons from patients harboring LRRK2 mutations. Here, we summarize biochemical and functional studies of LRRK2 and its mutations and focus on aberrant vesicular trafficking and protein synthesis as two leading mechanisms underlying LRRK2-linked disease.

Original languageEnglish (US)
Pages (from-to)554-565
Number of pages12
JournalJournal of Neurochemistry
Volume131
Issue number5
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Leucine
Parkinson Disease
Phosphotransferases
Mutation
Dopaminergic Neurons
Protein Transport
Neurons
Toxicity
Dopamine
Synucleins
Lewy Bodies
Biochemistry
Cytoskeletal Proteins
Penetrance
GTP Phosphohydrolases
Autophagy
Brain
Animals
Proteins
Animal Models

Keywords

  • Alpha-synuclein
  • GTPase
  • Kinase
  • Neurodegeneration
  • Protein translation
  • Rps15

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Martin, I., Kim, J. W., Dawson, V. L., & Dawson, T. M. (2014). LRRK2 pathobiology in Parkinson's disease. Journal of Neurochemistry, 131(5), 554-565. https://doi.org/10.1111/jnc.12949

LRRK2 pathobiology in Parkinson's disease. / Martin, Ian; Kim, Jungwoo Wren; Dawson, Valina L.; Dawson, Ted M.

In: Journal of Neurochemistry, Vol. 131, No. 5, 2014, p. 554-565.

Research output: Contribution to journalArticle

Martin, I, Kim, JW, Dawson, VL & Dawson, TM 2014, 'LRRK2 pathobiology in Parkinson's disease', Journal of Neurochemistry, vol. 131, no. 5, pp. 554-565. https://doi.org/10.1111/jnc.12949
Martin, Ian ; Kim, Jungwoo Wren ; Dawson, Valina L. ; Dawson, Ted M. / LRRK2 pathobiology in Parkinson's disease. In: Journal of Neurochemistry. 2014 ; Vol. 131, No. 5. pp. 554-565.
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