{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:15:34Z","timestamp":1791278134679,"version":"4.1.0"},"reference-count":56,"publisher":"Portland Press Ltd.","issue":"4","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,8,1]]},"abstract":"<jats:p>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 \u03b1-synuclein, parkin, ubiquitin C-ter-minal 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 \u03b1-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.<\/jats:p>","DOI":"10.1042\/bst0330586","type":"journal-article","created":{"date-parts":[[2005,8,3]],"date-time":"2005-08-03T12:51:58Z","timestamp":1123073518000},"page":"586-590","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Pathophysiology, pleotrophy and paradigm shifts: genetic lessons from Parkinson's disease"],"prefix":"10.1042","volume":"33","author":[{"given":"O.A.","family":"Ross","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.J.","family":"Farrer","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2005,8,1]]},"reference":[{"key":"2021111719351651600_B1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/ajmg.10335","volume":"109","author":"Maher","year":"2002","journal-title":"Am. 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