title: Novel genetic tools reveal Cdk5's major role in Golgi fragmentation in Alzheimer's disease.
abstract: Golgi fragmentation is a common feature in multiple neurodegenerative diseases; however, the precise mechanism that causes fragmentation remains obscure. A potential link between Cdk5 and Golgi fragmentation in Alzheimer's disease (AD) was investigated in this study. Because Golgi is physiologically fragmented during mitosis by Cdc2 kinase and current Cdk5-specific chemical inhibitors target Cdc2 as well, development of novel tools to modulate Cdk5 activity was essential. These enzyme modulators, created by fusing TAT sequence to Cdk5 activators and an inhibitor peptide, enable specific activation and inhibition of Cdk5 activity with high temporal control. These genetic tools revealed a major role of Cdk5 in Golgi fragmentation upon beta-amyloid and glutamate stimulation in differentiated neuronal cells and primary neurons. A crucial role of Cdk5 was further confirmed when Cdk5 activation alone resulted in robust Golgi disassembly. The underlying mechanism was unraveled using a chemical genetic screen, which yielded cis-Golgi matrix protein GM130 as a novel substrate of Cdk5. Identification of the Cdk5 phosphorylation site on GM130 suggested a mechanism by which Cdk5 may cause Golgi fragmentation upon deregulation in AD. As Cdk5 is activated in several neurodegenerative diseases where Golgi disassembly also occurs, this may be a common mechanism among multiple disorders.
authors.affiliation: Department of Chemistry and Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Kai-Hui
authors.initials: KH
authors.lastname: Sun
authors.forename: Yolanda
authors.initials: Y
authors.lastname: de Pablo
authors.forename: Fabien
authors.initials: F
authors.lastname: Vincent
authors.forename: Emmanuel O
authors.initials: EO
authors.lastname: Johnson
authors.forename: Angela K
authors.initials: AK
authors.lastname: Chavers
authors.forename: Kavita
authors.initials: K
authors.lastname: Shah
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D005821:Genetic Techniques; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D051360:Cyclin-Dependent Kinase 5; D016203:CDC2 Protein Kinase; C495905:CDK5 protein, human; C495907:Cdk5 protein, rat