Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 41, Pages 17004-17009Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1109356108
Keywords
protein misfolding; neurodegeneration
Categories
Funding
- National Institute for Health Research, Oxford Biomedical Research Centre
- Harvard Medical School
- National Institute for Health Research (Academic Clinical Lectureship Scheme, Oxford)
- WellcomeTrust/Academy of Medical Sciences
- Parkinson's UK
- Hereditary Disease Foundation
- Converging Research Center
- Korean government
- M.J. Fox Foundation, National Institute of General Medical Sciences
- National Institute for Aging
- WCU
- Parkinson's UK [K-0819, J-0901] Funding Source: researchfish
Ask authors/readers for more resources
alpha-Synuclein is an abundant brain protein that binds to lipid membranes and is involved in the recycling of presynaptic vesicles. In Parkinson disease, alpha-synuclein accumulates in intraneuronal inclusions often containing ubiquitin chains. Here we show that the ubiquitin ligase Nedd4, which functions in the endosomal-lysosomal pathway, robustly ubiquitinates alpha-synuclein, unlike ligases previously implicated in its degradation. Purified Nedd4 recognizes the carboxyl terminus of alpha-synuclein (residues 120-133) and attaches K63-linked ubiquitin chains. In human cells, Nedd4 overexpression enhances alpha-synuclein ubiquitination and clearance by a lysosomal process requiring components of the endosomal-sorting complex required for transport. Conversely, Nedd4 down-regulation increases alpha-synuclein content. In yeast, disruption of the Nedd4 ortholog Rsp5p decreases alpha-synuclein degradation and enhances inclusion formation and alpha-synuclein toxicity. In human brains, Nedd4 is present in pigmented neurons and is expressed especially strongly in neurons containing Lewy bodies. Thus, ubiquitination by Nedd4 targets alpha-synuclein to the endosomal- lysosomal pathway and, by reducing alpha-synuclein content, may help protect against the pathogenesis of Parkinson disease and other alpha-synucleinopathies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available