Science-2016-Bee happy英文书.pdfVIP

PHOTO: SMUDGE 9000/FLICKR Downloaded from / on September 29, 2016 mechanisms may vary between pathogenic proteins or even between cells (13). However, interfering with any stage has the potential to block the spreading and neurotoxicity of proteopathic lesions (1, 13). It will be important to determine whether LAG3 is simply a cellsurface binding protein that mediates the uptake of pathogenic a-synuclein, or whether LAG3 might mediate further intracellular trafficking or signaling or propagation of aggregates. Another crucial step in transmission is the exit of pathogenic a-synuclein from cells. Strikingly, an unconventional deubiquitylase USP19-dependent secretion pathway for misfolded cytoplasmic proteins, including misfolded a-synuclein but not tau (14), suggests that the mechanisms for uptake and release may be very specific for given proteopathic aggregates. In Parkinson’s disease, a-synuclein aggregation in the brain begins many years before the onset of symptoms (15). Thus, interfering with the a-synuclein cascade is likely to be most effective when initiated at an early preclinical stage. LAG3-blocking antibodies were used by Mao et al., and anticancer agents that block LAG3 have been developed to overcome immunosuppressive mechanisms within the tumor microenvironment (9). However, to minimize the risk of autoimmune or hyperimmune activation phenotypes, very specific suppression of LAG3 in the brain is needed if this protein is to be safely targeted in the treatment of brain diseases. If LAG3 is confirmed to be a receptor for pathogenic a-synuclein, it will be important to define the structural requirements for binding and the nature of the pathogenic asynuclein species that binds LAG3. Although many important issues remain to be resolved, the remarkable interaction of LAG3 and aggregated a-synuclein calls for additional research to determine the physiological function of LAG3 in the brain and to evaluate the potential of LAG3 as a therapeutic target for mod