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| Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase |
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| Author(s): Ramirez A (Ramirez, Alfredo), Heimbach A (Heimbach, Andre), Gruendemann J (Gruendemann, Jan), Stiller B (Stiller, Barbara), Hampshire D (Hampshire, Dan), Cid LP (Cid, L. Pablo), Goebel I (Goebel, Ingrid), Mubaidin AF (Mubaidin, Ammar F.), Wriekat AL (Wriekat, Abdul-Latif), Roeper J (Roeper, Jochen), Al-Din A (Al-Din, Amir), Hillmer AM (Hillmer, Axel M.), Karsak M (Karsak, Meliha), Liss B (Liss, Birgit), Woods CG (Woods, C. Geoffrey), Behrens MI (Behrens, Maria I.), Kubisch C (Kubisch, Christian) |
| Source: NATURE GENETICS Volume: 38 Issue: 10 Pages: 1184-1191 Published: OCT 2006 |
| Times Cited: 125 References: 30 |
| Abstract: Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders(1). Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases(2). This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system(3-6). Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-on-set parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome(7,8)). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity(9) to the protein networks implicated in neurodegeneration and parkinsonism. |
| Document Type: Article |
| Language: English |
| Reprint Address: Kubisch, C (reprint author), Univ Cologne, Inst Human Genet, D-50931 Cologne, Germany |
Addresses:
1. Univ Cologne, Inst Human Genet, D-50931 Cologne, Germany
2. Univ Cologne, Inst Genet, D-50931 Cologne, Germany
3. Univ Cologne, Ctr Mol Med, D-50931 Cologne, Germany
4. Univ Bonn, Inst Human Genet, D-53111 Bonn, Germany
5. Univ Marburg, Inst Physiol, D-35037 Marburg, Germany
6. Univ Leeds, Mol Med Unit, Leeds LS9 7TF, W Yorkshire England
7. Ctr Estudios Cient, Valdivia 5099100, Chile
8. King Hussein Med Ctr, Dept Neurol, Amman 11947, Jordan
9. Pinderfields Hosp, Dept Neurol, Wakefield WF1 4DG, England
10. Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany
11. Univ Bonn, Life & Brain Ctr, Dept Mol Psychiat, D-53127 Bonn, Germany
12. Cambridge Inst Med Res, Cambridge CB2 2QQ, England
13. Univ Chile, Dept Neurol & Neurosurg, Santiago 8207257, Chile |
| Publisher: NATURE PUBLISHING GROUP, 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA |
| Subject Category: Genetics & Heredity |
| IDS Number: 094PJ |
| ISSN: 1061-4036 |
| DOI: 10.1038/ng1884 |
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