New study uncovers how brain cells degrade dangerous protein aggregates
Researchers at the RIKEN Brain Science Institute (BSI) have discovered a key mechanism responsible for selectively degrading aggregates of ubiquitinated proteins from the cell. Their findings indicate that the capture and removal of such aggregates is mediated by the phosphorylation of a protein called p62, opening the door to new avenues for treating neurodegenerative diseases such as Huntington's disease and Alzheimer's disease.
Polyubiquitinated proteins confined inside a "sequestome" prior to autophagy.
One of the most important activities of a cell is the production of proteins, which play essential functions in everything from oxygen transport, to immune defense, to food digestion. Equally important to the cell's survival is how it deals with these proteins when they pass their expiry date: damaged or misfolded proteins have been associated with a range of debilitating conditions, including neurodegenerative diseases such as Alzheimer's disease.
In eukaryotic cells, the recycling of damaged or misformed proteins is governed by a small regulatory protein called ubiquitin in a process called "ubiquitination". By attaching itself to a protein, a ubiquitin molecule can tag the protein for destruction by proteasomes, large protein complexes that degrade and recycle unneeded proteins in the cell. This recycling of proteins by proteasomes is crucial to the maintenance of cellular homeostasis.
With their research, the BSI research group sought to shed light on one area where proteasome-based recycling falls short: protein complexes or aggregates, which proteasomes have trouble degrading. The group shows that this weakness is made up for by the phosphorylation of a protein called p62 at the serine 403 (S403) loci of its ubiquitin-associated (UBA) domain, which triggers a catabolic process called selective autophagy that degrades protein aggregates. It does this by forming a "sequestosome", a structure which sequesters polyubiquitinated protein aggregates in preparation for autophagy. (Figure 1)
Published in the journal Molecular Cell, the discovery of this mechanism opens the door to the development of new, more effective drugs for selectively degrading protein aggregates, promising applications in the treatment of a range of neurodegenerative diseases.
- For more information, please contact
- Nobuyuki Nukina
- Laboratory for Structural Neuropathology
- RIKEN Brain Science Institute
- Tel: +81-(0)48-467-9702 / Fax: +81-(0)48-462-4796
- Gen Matsumoto
- Laboratory for Structural Neuropathology
- RIKEN Brain Science Institute
- Tel: +81-(0)48-462-1111 / Fax: +81-(0)48-462-4796
- Global Relations Office
- RIKEN
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Reference:
Gen Matsumoto, Koji Wada, Misako Okuno, Masaru Kurosawa, and Nobuyuki Nukina."Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins." Molecular Cell, 2011, DOI: 10.1016/j.molcel.2011.07.039
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RIKEN is Japan's flagship research institute devoted to basic and applied research. Over 2500 papers by RIKEN researchers are published every year in reputable scientific and technical journals, covering topics ranging across a broad spectrum of disciplines including physics, chemistry, biology, medical science and engineering. RIKEN's advanced research environment and strong emphasis on interdisciplinary collaboration has earned itself an unparalleled reputation for scientific excellence in Japan and around the world.
About the Brain Science Institute
The RIKEN Brain Science Institute (BSI) was established as an institute at RIKEN in October, 1997 to answer a growing need in society for cutting-edge brain science research. Since its establishment, BSI has attracted promising scientists domestically and internationally and brought together diverse research and human resources, and today enjoys an international reputation as an innovative center for brain science.
Research at BSI integrates a wide range of disciplines including medicine, biology, physics, technology, information science, mathematical science, and psychology. BSI's research objectives cover individual organisms, behavior, microscopic molecular structures of the brain, neurons, neurocircuits, cognition, memory, learning, language acquisition, and robotics.
Figure 1 Model for p62-mediated selective autophagy pathway.