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.

Public Health Relevance

Protein depalmitoylation is the removal of C16 fatty acid from cysteines on proteins. Over 500 proteins in brains are dynamically palmitoylated and depalmitoylated. In this study, we will characterize the substrates of PPT1, the major depalmitoylating enzyme and examine how loss of PPT1 activity leads to neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS094971-01A1
Application #
9111168
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Morris, Jill A
Project Start
2016-03-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Gorenberg, Erica L; Chandra, Sreeganga S (2017) The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease. Front Neurosci 11:248