Autosomal recessive juvenile parkinsonism: A key to understanding nigral degeneration in sporadic Parkinson's disease

• Published in: Neuropathology 2000-09, Vol.20 (s1), p.85-90
• Main Authors: Hattori, Nobutaka, Shimura, Hideki, Kubo, Shin-ichiro, Kitada, Tohru, Wang, Mei, Asakawa, Shuichi, Minashima, Shinsei, Shimizu, Nobuyoshi, Suzuki, Toshiaki, Tanaka, Keiji, Mizuno, Yoshikuni
• Format: Article
• Language: English
• Subjects: a-synuclein; autosomal recessive juvenile parkinsonism; Chromosomes, Human, Pair 6 - physiology; DNA Mutational Analysis; familial Parkinson's disease; genetic factor; Humans; inclusion bodies; Lewy bodies; Ligases; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - physiopathology; parkin; Parkinsonian Disorders - genetics; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - physiopathology; Proteins - genetics; Proteins - metabolism; Substantia Nigra - metabolism; Substantia Nigra - pathology; Substantia Nigra - physiopathology; ubiquitin carboxy-terminal hydrolase L1; ubiquitin pathway; Ubiquitin-Protein Ligases; α-synuclein
• ISSN: 0919-6544; 1440-1789
• DOI: 10.1046/j.1440-1789.2000.00312.x

The contribution of genetic factors to the pathogenesis of Parkinson's disease (PD) is supported by the demonstration of the high concordance in twins studies using positron emission tomography (PET), the increased risk among relatives of PD patients in case–control and family studies, and the existence of familial PD and parkinsonism by single gene defect. Recently several genes have been mapped and/or identified. α‐Synuclein is involved in a rare dominant form of familial PD with dopa‐responsive parkinsonism features and Lewy body‐positive pathology. In contrast, parkin is responsible for the autosomal recessive form (AR‐JP) of early onset PD with Lewy body‐negative pathology. The clinical features of this form include early onset (in the 20s), levodopa‐responsive parkinsonism, diurnal fluctuation, and slow progression of the disease. Parkin consists of 12 exons and the estimated size is over 1.5 Mb. To date, variable mutations such as deletions or point mutations resulting in missense and nonsense changes have been reported in AR‐JP patients. In addition, the localization of parkin indicates that parkin may be involved in the axonal transport system. More recently we have found that parkin interacts with the ubiquitin‐conjugating enzyme E2 and is functionally linked to the Ub‐proteasome pathway as a ubiquitin ligase, E3. These findings fit the characteristics of a lack of Lewy bodies (these are cytoplasmic inclusions that are considered to be a pathological hallmark). Our findings should enhance the exploration of the mechanisms of neuronal death in PD as well as other neurodegenerative disorders of which variable inclusion bodies are observed.