Genetics of Parkinsonism

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Some debate still exists as to whether PD is predominantly environmental or genetic in etiology. The genetic hypothesis of PD etiology has been driven recently by the identification of a number of PD loci. This review deals with each of these loci, discussing the latest data and evidence available. Of particular interest are the recently described mutations in the PINK1 (PARK6) and LRRK2 (PARK8) genes. We also consider the impact of these latest developments on our understanding of sporadic PD and on our everyday practice with PD patients.

Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration

“…The gene product has also been termed ''Dardarin.'' Several different point mutations segregate with the PD phenotype in families, including the original PARK8 family (17)(18)(19)(20)(21)(22), and they are found also in some sporadic PD cases (23). Patients with LRRK2 mutations have typical relatively late onset Parkinsonism with features comparable with idiopathic PD, with asymmetric rest tremor, bradykinesia, rigidity, and a good response to 3,4-dihyroxy-L-phenylalanine (L-DOPA) (15,24).…”

Neuropsychiatric and cognitive features in autosomal‐recessive early parkinsonism due to PINK1 mutations

“…The important role of genetics in the etiology of Parkinson's disease (PD) is becoming increasingly recognized 1. At present, 10 loci have been identified, representing genomic regions linked to Mendelian forms of PD, five of which (PARK 1, 2, 6, 7, and 8) have been shown to contain gene mutations 2–6. Among the autosomal‐recessive early‐onset parkinsonian (AREP) disorders, PTEN‐induced kinase 1 or PINK1 (PARK6) is the second in prevalence 7.…”

Neurodegeneration and cell replacement

“…Many genetic mutations are now evident in familial cases of PD (Lewthwaite & Nicholl 2005). Genetic PD models include a-synuclein knockout mice and transgenic mice over-expressing the mutant human a-synuclein protein.…”