Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation

Biochem Soc Trans. 2017 Feb 8;45(1):163-172. doi: 10.1042/BST20160264.


Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD) with autosomal dominant inheritance. Accordingly, LRRK2 has emerged as a promising therapeutic target for disease modification in PD. Since the first discovery of LRRK2 mutations some 12 years ago, LRRK2 has been the subject of intense investigation. It has been established that LRRK2 can function as a protein kinase, with many putative substrates identified, and can also function as a GTPase that may serve in part to regulate kinase activity. Familial mutations influence both of these enzymatic activities, suggesting that they may be important for the development of PD. Many LRRK2 models have been established to understand the pathogenic effects and mechanisms of familial mutations. Here, we provide a focused discussion of the evidence supporting a role for kinase and GTPase activity in mediating the pathogenic effects of familial LRRK2 mutations in different model systems, with an emphasis on rodent models of PD. We also critically discuss the contribution and relevance of protein aggregation, namely of α-synuclein and tau-proteins, which are known to form aggregates in PD brains harboring LRRK2 mutations, to neurodegeneration in LRRK2 rodent models. We aim to provide a clear and unbiased review of some of the key mechanisms that are important for LRRK2-dependent neurodegeneration in PD.

Keywords: Parkinson's disease; cell death; enzyme activity; leucine-rich repeat kinase; neurodegeneration; protein aggregation.

Publication types

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

MeSH terms

  • GTP Phosphohydrolases / genetics*
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Models, Genetic
  • Mutation*
  • Neurodegenerative Diseases / enzymology
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Protein Aggregates
  • Protein Aggregation, Pathological
  • alpha-Synuclein / metabolism
  • tau Proteins / metabolism


  • Protein Aggregates
  • alpha-Synuclein
  • tau Proteins
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • GTP Phosphohydrolases