Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein

Neuron. 2009 Dec 24;64(6):807-27. doi: 10.1016/j.neuron.2009.11.006.

Abstract

Mutations in alpha-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice, which likely resulted from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that overexpression of LRRK2 enhances alpha-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / physiopathology
  • Disease Progression
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease / genetics
  • Golgi Apparatus / metabolism
  • Golgi Apparatus / ultrastructure
  • Inclusion Bodies / genetics
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microtubules / metabolism
  • Microtubules / ultrastructure
  • Mutation / genetics
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / physiopathology
  • Neurons / metabolism
  • Neurons / pathology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / physiopathology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • alpha-Synuclein
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • Protein-Serine-Threonine Kinases