Identifying the neuronal substrates of the depalmitoylating enzyme PPT1

鉴定去棕榈酰化酶 PPT1 的神经元底物

• 批准号: 9111168
• 负责人: Sreeganga S Chandra
• 金额: $ 25.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111168
• 关键词: Adult; Biology; Brain; Cellular biology; Cessation of life; Chemistry; Clinical; Cysteine; Data; Disease; Electric Stimulation; Enzymes; Excision; Family; Fatty Acids; Goals; Harvest; Health; Human; Impaired cognition; Individual; Infantile neuronal ceroid lipofuscinosis; Kainic Acid; Knock-in; Knock-out; Knockout Mice; Knowledge; Label; Link; Lipids; Mass Spectrum Analysis; Methods; Modification; Monitor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neuronal Ceroid-Lipofuscinosis; Neurons; Palmitates; Pathology; Patients; Peptides; Play; Post-Translational Protein Processing; Proteins; Proteomics; Research; Residual state; Role; Seizures; Signal Transduction Pathway; Staging; Synapses; Synaptic plasticity; Synaptosomes; Testing; Therapeutic Intervention; Time; Transferase; Visual; base; effective therapy; farnesylation; infancy; insight; isoprenylation; loss of function mutation; motor impairment; mouse model; neuronal cell body; palmitoylation; premature; presynaptic; progressive neurodegeneration; protein degradation; research study; response; thioesterase PPT1 gene product

 DESCRIPTION (provided by applicant): Palmitoylation is the covalent attachment of C16 fatty acids to proteins. Palmitoylation is a dynamic post- translational modification and unlike other stable lipid modifications (isoprenylation, farnesylation). One of the major enzymes that remove this lipid modification is palmitoyl protein thioesterase 1 (PPT1). Recessive loss-of-function mutations in PPT1 cause Neuronal Ceroid Lipofuscinosis (NCL), a progressive neurodegenerative disease with lysosomal pathology. Complete loss of PPT1 enzymatic activity leads to an infantile form of the disease, while residual activity (5-10%) leads to adult-onset NCL. Patients accumulate lipidated peptides suggesting that deficient depalmitoylation leads to compromised protein degradation. These clinical findings strongly suggest that PPT1 activity is critical for neuronal function and health. Despite its importance, the substrates of PPT1 remain to be defined. In this proposal, we aim to identify PPT1 substrates based on an unbiased proteomic screen comparing the palmitomes of wildtype and PPT1 knockout brains. Then, we will examine which of these substrates are depalmitoylated in response to neuronal activity. These experiments will delineate an important, yet understudied, aspect of neuronal cell biology and elucidate the mechanisms of NCL. Achieving these goals is important for human health, given the direct links between PPT1 and NCL as well as the wide range of neurodegenerative disorders that involve protein palmitoylation.