Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson's disease.
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 alpha-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 alpha-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.
Ross
O A
OA
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Farrer
M J
MJ
D006801:Humans; D008958:Models, Molecular; D008959:Models, Neurological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology*; D011487:Protein Conformation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D009419:Nerve Tissue Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein