LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson's disease: a review

J Biomed Sci. 2018 Jun 14;25(1):52. doi: 10.1186/s12929-018-0454-0.


Parkinson's disease (PD) is the most common movement disorder and manifests as resting tremor, rigidity, bradykinesia, and postural instability. Pathologically, PD is characterized by selective loss of dopaminergic neurons in the substantia nigra and the formation of intracellular inclusions containing α-synuclein and ubiquitin called Lewy bodies. Consequently, a remarkable deficiency of dopamine in the striatum causes progressive disability of motor function. The etiology of PD remains uncertain. Genetic variability in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of sporadic and familial PD. LRRK2 encodes a large protein containing three catalytic and four protein-protein interaction domains. Patients with LRRK2 mutations exhibit a clinical and pathological phenotype indistinguishable from sporadic PD. Recent studies have shown that pathological mutations of LRRK2 can reduce the rate of guanosine triphosphate (GTP) hydrolysis, increase kinase activity and GTP binding activity, and subsequently cause cell death. The process of cell death involves several signaling pathways, including the autophagic-lysosomal pathway, intracellular trafficking, mitochondrial dysfunction, and the ubiquitin-proteasome system. This review summarizes the cellular function and pathophysiology of LRRK2 ROCO domain mutations in PD and the perspective of therapeutic approaches.

Keywords: GTPase activity; LRRK2; Parkinson’s disease; ROCO domain; Signaling pathway.

Publication types

  • Review

MeSH terms

  • Dopamine / genetics*
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Mutation
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Protein Domains / genetics
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology


  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Dopamine