A protein linked to Parkinson's disease may cause neurodegeneration by inhibiting autophagy--the process in which cells digest some of their contents--according to a study in the September 20 issue of the Journal of Cell Biology (www.jcb.org).
Autophagy serves to clear a variety of toxic waste from cells, including misfolded proteins and defective mitochondria. These two types of cellular trash accumulate in neurons from Parkinson's patients, suggesting that autophagy could be impaired in these cells. A commonly amassed protein in Parkinson's disease is alpha-synuclein, whose gene is often mutated or overexpressed in familial forms of the illness. David Rubinsztein and researchers from the University of Cambridge in England found that excess alpha-synuclein inhibits autophagy by blocking formation of the autophagosome--the double-membraned vesicle that engulfs cytoplasmic garbage and delivers it to lysosomes for destruction.
Previous research revealed that alpha-synuclein inhibits Rab1a, a small GTPase that controls secretory transport from the Endoplasmic Reticulum to the Golgi. Rubinsztein and colleagues now provide new insight into the role Rab1a plays in autophagy, and why blocking it has such dire consequences. The team found that lack of Rab1a impaired autophagosome formation, whereas an abundance of the GTPase reversed the inhibitory effects of alpha-synuclein on autophagy. Rab1a and alpha-synuclein act specifically at an early stage of autophagosome formation: an abundance of alpha-synuclein or lack of Rab1a disrupted an early acting part of the autophagy machinery called Atg9 and blocked the formation of autophagosome precursors known as omegasomes.
Alpha-synuclein's blockade of autophagy could enhance the gradual accumulation of toxic proteins and dysfunctional mitochondria, sensitizing neurons to cell death.
About The Journal of Cell Biology
Founded in 1955, The Journal of Cell Biology (JCB) is published by The Rockefeller University Press. All editorial decisions on manuscripts submitted are made by active scientists in conjunction with our in-house scientific editors. JCB content is posted to PubMed Central, where it is available to the public for free six months after publication. Authors retain copyright of their published works and third parties may reuse the content for non-commercial purposes under a creative commons license. For more information, please visit www.jcb.org.
Winslow, A.R., et al. 2010. J. Cell Biol. doi:10.1083/jcb.201003122.
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.