Pathophysiology, pleotrophy and paradigm shifts: Genetic lessons from Parkinson's disease

O. A. Ross, M. J. Farrer

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


PD (Parkinson's disease) is an aetiologically heterogeneous disorder characterized by a clinical phenotype consisting of resting tremor, rigidity and bradykinesia. Motor symptoms are associated with a progressive loss of dopaminergic neurons, with Lewy body inclusions within surviving neurons. Although heritability studies have shown evidence of familial aggregation, twin studies have provided limited support for a genetic aetiology. Nevertheless, classical linkage methods have nominated 11 regions of the genome and pathogenic mutations have been identified in several genes, including α-synuclein, parkin, ubiquitin C-terminal hydrolase L1, oncogene DJ-1, PTEN-induced protein kinase 1 and microtubule-associated protein tau. Most recently, heterozygous mutations in LRRK2 (leucine-rich repeat kinase 2) were found to cause late-onset, autosomal-dominant PD. Despite their consistent clinical phenotype, family members with LRRK2 mutations can have variable α-synuclein and tau pathologies. Lrrk2 is a member of the Roc (Ras of complex proteins) family, with Ras GTPase and MAPKKK (mitogen-activated protein kinase kinase kinase) catalytic domains. Thus its discovery highlights vesicle dynamics and secondary-messenger signalling in disease pathophysiology. To diagnose a disease accurately and effectively treat it, requires an understanding of its molecular pathogenesis. Herein, we provide an overview of the genetics of PD, how these discoveries are revolutionizing long-held beliefs and more importantly how this knowledge may be translated into patient therapy.

Original languageEnglish (US)
Pages (from-to)586-590
Number of pages5
JournalBiochemical Society Transactions
Issue number4
StatePublished - Aug 2005


  • Genetics
  • LRRK2
  • Neurodegeneration
  • Parkinsonism
  • Pathophysiology
  • Pleotrophy

ASJC Scopus subject areas

  • Biochemistry


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