Synuclein aggregation in dopaminergic neurons is a hallmark of Parkinson's disease (PD) pathology. The most common genetic risk factor for PD is glucocerebrosidase (GBA) mutation with as many as 7% of PD patients carrying this mutation. Work to date has primarily focused on the loss of GBA enzymatic activity that could contribute to ?-synuclein accumulation and/or aggregation. However, evidence has indicated that improperly folded mutant GBA could also contribute to the ?-synuclein aggregation independent of the loss of enzymatic activity. Our central hypothesis is that mutant GBA is mistargeted from lysosomes to the cytosol, which interferes with ?-synuclein degradation by chaperone-mediated autophagy (CMA). We will test this hypothesis with a combination of biochemical, cell biological, mouse genetics, and neuropath logical techniques in several systems including isolated lysosomes, mouse models, post-mortem human brain, and fibroblasts from patients'skin biopsy. Our research strategies are divided into three specific aims:
Aim 1 will investigate the mechanism by which mutant GBA attenuates CMA and leads to ?-synuclein accumulation by examining each step of CMA in an in vitro system using isolated lysosomes, purified mutant GBA and ?- synuclein proteins.
Aim 2 will study whether CMA alteration occurs in GBA-mutant mouse models by using a novel CMA reporter in neuronal cultures and determine whether the protein levels of CMA machinery components change in GBA-mutant mouse models and post-mortem PD brain with GBA mutations.
Aim 3 will determine CMA activity using the reporter in the skin fibroblasts from PD patients with GBA mutations, PD patients without GBA mutations, and age-matched controls. These data will provide evidence on whether mutant GBA causes CMA dysfunction, leading to ?-synuclein aggregation, and whether CMA dysfunction is a typical feature of PD. The proposed study could contribute to the future identification of mechanism-based biomarker and therapeutic targets. This K08 proposal also outlines a detailed 5-year training program with specific formal coursework and structured mentoring for the candidate, Sheng-Han Kuo, M.D. The proposed work will be carried out in the Department of Neurology at Columbia University, an excellent environment for training physician-scientists. He will receive the necessary training under the mentorship of Drs. David Sulzer, Ana Maria Cuervo, and Karen Marder, world-renowned investigators in the PD field and acquire necessary skill set to become an independent researcher. The long-term goal of the candidate is to be a translational physician-scientist to investigate the mechanism underlying PD pathology and to develop clinical applicable biomarkers for PD.

Public Health Relevance

Parkinson's disease (PD) is the second most common neurodegenerative disorders and currently there is no effective treatment for the underlying neurodegeneration in PD. Understanding the common mechanism of genetic PD pathology could potentially lead to the identification of useful biomarkers and therapies for PD patients

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Study Section
NST-2 Subcommittee (NST)
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Sutherland, Margaret L
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Woodard, Chris M; Campos, Brian A; Kuo, Sheng-Han et al. (2014) iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease. Cell Rep 9:1173-82
Hua, Ping; Liu, Weiguo; Chen, Donghui et al. (2014) Cry1 and Tef gene polymorphisms are associated with major depressive disorder in the Chinese population. J Affect Disord 157:100-3
Goldman, Jill S; Kuo, Sheng-Han (2014) Multiple system atrophy and repeat expansions in C9orf72--reply. JAMA Neurol 71:1191-2
Louis, Elan D; Kuo, Sheng-Han; Vonsattel, Jean-Paul G et al. (2014) Torpedo formation and Purkinje cell loss: modeling their relationship in cerebellar disease. Cerebellum 13:433-9
Wang, Hualong; Lian, Kaoqi; Han, Bing et al. (2014) Age-related alterations in the metabolic profile in the hippocampus of the senescence-accelerated mouse prone 8: a spontaneous Alzheimer's disease mouse model. J Alzheimers Dis 39:841-8
Lin, Chi-Ying; Louis, Elan D; Faust, Phyllis L et al. (2014) Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 137:3149-59
Goldman, Jill S; Quinzii, Catarina; Dunning-Broadbent, Jane et al. (2014) Multiple system atrophy and amyotrophic lateral sclerosis in a family with hexanucleotide repeat expansions in C9orf72. JAMA Neurol 71:771-4