Fast axonal transport misregulation and Alzheimer's disease.
Pathological alterations in the microtubule-associated protein (MAP) tau are well-established in a number of neurodegenerative disorders, including Alzheimer's Disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. Tau protein and in some cases, neurofilament subunits exhibit abnormal phosphorylation on specific serine and threonine residues in these diseases. A large body of biochemical, genetic, and cell biological evidence implicate two major serine-threonine protein kinases, glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase 5 (CDK5) as major kinases responsible for both normal and pathological phosphorylation of tau protein in vivo. What remains unclear is whether tau phosphorylation and/or neurofibrillary tangle (NFT) formation are causal or secondary to initiation of neuronal pathology. In fact, many studies have indicated that tau misphosphorylation is not the causal event. Interestingly, some of these kinase and phosphatase activities have recently merged as key regulators of fast axonal transport (FAT). Specifically, CDK5 and GSK-3 have been recently shown to regulate kinesin-driven motility. Given the essential role of FAT in neuronal function, an alternate model for pathogenesis can be proposed. In this model, misregulation of FAT induced by an imbalance in specific kinase-phosphatase activities within neurons represents an early and critical step for the initiation of neuronal pathology. Such a model may explain many of the unique characteristics of late onset of neurological diseases such as AD.
Morfini
Gerardo
G
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas 75390-9039, USA.
Pigino
Gustavo
G
Beffert
Uwe
U
Busciglio
Jorge
J
Brady
Scott T
ST
D000544:Alzheimer Disease / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins