New study uncovers how brain cells degrade dangerous protein aggregates

Figure 1: Model for p62-mediated selective autophagy pathway. Credit: RIKEN

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.

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 such as Alzheimer's disease.

In eukaryotic cells, the recycling of damaged or misformed proteins is governed by a small 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 .

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.

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 , promising applications in the treatment of a range of neurodegenerative diseases.

add to favorites email to friend print save as pdf

Related Stories

Self-digestion as a means of survival

Feb 27, 2009

In times of starvation, cells tighten their belts: they start to digest their own proteins and cellular organs. The process - known as autophagy - takes place in special organelles called autophagosomes. It is a strategy ...

Neurodegeneration 'clumping proteins' common in aging process

Aug 10, 2010

Many proteins that form insoluble clumps in the brains of people with Alzheimer's and other neurodegenerative diseases are also found in healthy individuals and clump together as a normal part of aging. According to a surprising ...

Recommended for you

Leeches help save woman's ear after pit bull mauling

1 minute ago

(HealthDay)—A pit bull attack in July 2013 left a 19-year-old woman with her left ear ripped from her head, leaving an open wound. After preserving the ear, the surgical team started with a reconnection ...

New pain relief targets discovered

11 hours ago

Scientists have identified new pain relief targets that could be used to provide relief from chemotherapy-induced pain. BBSRC-funded researchers at King's College London made the discovery when researching ...

Building 'smart' cell-based therapies

12 hours ago

A Northwestern University synthetic biology team has created a new technology for modifying human cells to create programmable therapeutics that could travel the body and selectively target cancer and other ...

User comments