Putting proteins in their place: Palmitoylation in Huntington disease and other neuropsychiatric diseases

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• 作者：Fiona B. Young ; Stefanie L. Butland¹ ; Shaun S. Sanders¹ ; Liza M. Sutton¹ ; Michael R. Hayden ; ^{mrh@cmmt.ubc.ca}
• 关键词：AD ; Alzheimer disease ; HD ; Huntington disease ; PAT ; palmitoylacyltransferase ; PTM ; post-translational modification ; TMD ; transmembrane domain ; PM ; plasma membrane ; ER ; endoplasmic reticulum
• 刊名：Progress in Neurobiology
• 出版年：2012
• 期刊代码：62_03010082
• 类别：neu
• 出版时间：May, 2012
• 卷：97
• 期：2
• 页码：220-238
• 文件大小：1351 K

摘要

Post-translational modification of proteins by the lipid palmitate is critical for protein localization and function. Palmitoylation is regulated by the opposing enzymes palmitoyl acyltransferases (PATs) and acyl protein thioesterases, which add and remove palmitate from proteins, respectively. Palmitoylation is particularly important for a number of processes including neuronal development and synaptic activity in the central nervous system. Dysregulated palmitoylation contributes to neuropsychiatric disease. In total six PATs (HIP14, HIP14L, ZDHHC8, ZDHHC9, ZDHHC12, and ZDHHC15) and one thioesterase (PPT1) have been implicated in Huntington disease (HD), Alzheimer disease, schizophrenia, mental retardation, and infantile and adult onset forms of neuronal ceroid lipofuscinosis. Currently there is no genetic link between PATs and Alzheimer disease pathogenesis but palmitoylation of amyloid precursor protein-processing enzyme, 纬-secretase, influences 尾-amyloid generation. Several lines of evidence point to a role for palmitoylation by HIP14 in the pathogenesis of HD; HIP14 is dysfunctional in the presence of the HD mutation and Hip14-deficient mice develop features of HD. Wildtype huntingtin (the protein mutated in HD) enhances the PAT activity of HIP14 and mutant HTT interacts less with HIP14. Therefore, it may be that loss of the positive modulation of HIP14 activity due to reduced interaction with huntingtin is important in the disease mechanism. Preliminary evidence suggests a closely related PAT to HIP14, HIP14L, may also play a role in the pathogenesis of HD. In order to design rational therapeutic approaches to restore palmitoylation in neuropsychiatric disease, it will be critical to better understand the relationships between PATs and thioesterases with their regulators and substrates.