Endocytic mechanisms and drug discovery in neurodegenerative diseases.
Extensive research has been carried out to elucidate the mechanism of neurodegenerative diseases, with special emphasis on lysosomal storage disease (LSD) and Alzheimer's disease (AD). Studies have outlined complicated profiles in both types of disorders for the role of endocytosis in disease pathogenesis and progression. Recent discoveries relating endocytosis to the pathological origin and therapeutic strategy of the diseases have yet to be addressed. In this review, I attempt to demonstrate a comprehensive analysis on the endocytic mechanism of the disease. I propose that LSD could be classified as a late endosomal trafficking disorder. I also highlight that the most critical cellular event in AD--the producing, processing, and trafficking of Abeta42 peptide--dynamically involves the entire endocytic system. I further analyze pipeline drug targets, summarize the development status of current new drugs, share thoughts on potential therapeutic strategies, and reveal that many such strategies are in close association with endocytosis. I emphasize that thoroughly understanding pathologically-relevant endocytic events is the key factor in speeding up discovery and development of novel drugs.
Department of Biology, Synta Pharmaceuticals, 125 Hartwell Avenue, Lexington, MA 02421, USA. mzhang@syntapharma.com
Mei
M
Zhang
D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D002450:Cell Communication; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000188:drug therapy / Q000503:physiopathology; D008322:Mammals; D009410:Nerve Degeneration / Q000503:physiopathology / Q000517:prevention & control; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000502:physiology; D013572:Synaptic Vesicles / Q000502:physiology
D004791:Enzyme Inhibitors