Parkinson's disease (PD) is characterized by the presence of Lewy body inclusions in the nervous system comprised of insoluble alpha-synuclein (a-syn). The mechanisms that dictate the conversion of a-syn from its physiological state into pathogenic aggregates are not completely understood. Genetic studies have provided clues into the etiology of PD and causative factors that might promote a-syn inclusions. Among these, mutations in the lysosomal system have emerged as key risk factors for PD. Since lysosomes can degrade physiological a-syn, loss-of-lysosomal function may promote a-syn accumulation and drive aggregation. Mutations in lysosomal GBA1 have been identified as the strongest risk factor in PD, and are also highly associated with early onset dementia in PD patients. GBA1 mutations are also strong risk factors for a related synucleinopathy, Dementia with Lewy bodies (odds ratio=8.28), that often involves the co-aggregation of other disease-linked proteins linked to Alzheimer's disease such as tau and A?. GBA1 encodes lysosomal beta- Glucocerebrosidase (GCase), which degrades glucosylceramide (GluCer) in lysosomes. Homozygous GBA1 mutations cause the rare lysosomal storage disorder, Gaucher's disease (GD), which is also characterized by Lewy body inclusions in the nervous system. All of the GD or PD associated mutations identified to date have been well characterized and cause loss-of-enzymatic function. Additionally, GluCer substrate accumulation has been documented in patient-derived tissues and iPS neurons of both diseases. Our previous studies have indicated that GluCer directly converts physiological a-syn conformers into pathogenic assembly-state species in GD iPSn models and patient derived midbrain neurons. Here, we propose to study the mechanism of GluCer-induced aggregation by examining the how aggregates propagate and persist in human iPSn models. Pathogenic a-syn oligomers persist for hundreds of days in patient-derived iPS neurons, and our studies will examine potential mechanisms to explain this phenomenon. We will determine if the unique conformational information of GluCer-induced oligomers can be replicated by interaction and conversion of physiological conformers, their ability to cross-seed aggregates with tau or A?, neuron-to-neuron dissemination, and transmission of metabolic dysfunction. It is well known that PD and other synucleinopathies demonstrate remarkable heterogeneity for which there is no mechanistic explanation. Our studies will begin to examine this process by testing the cross-seeding potential of GluCer-induce a-syn oligomers. We plan to study these processes in human iPS midbrain models, established cell lines, and mouse models of GD. We will relate GluCer induced changes in pathological a-syn to comorbid pathologies and neuronal toxicity in vitro and in vivo. If successful, these studies will provide novel insight into the mechanisms of GBA1-associated PD, they may help to explain the high frequency of dementia and disease heterogeneity in PD patients, and may help to provide novel therapeutics to eliminate pathogenic propagation induced by glycosphingolipids.

Public Health Relevance

Neurodegenerative disorders such as Parkinson's disease are characterized by the accumulation of insoluble protein inclusions made of alpha-synuclein, although the mechanisms that permit the persistence of inclusions are not known. Furthermore, clinical and pathological disease comorbidity, such as dementia, frequently occurs with PD for unknown reasons. We propose to use patient-derived midbrain cultures and other models to examine mechanisms that lead to protein accumulation and disease comorbidity, including prion-like replication and spreading, heterologous cross-seeding of tau and A?, and lysosomal dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS109157-01
Application #
9640047
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2019-03-01
Project End
2024-02-28
Budget Start
2019-03-01
Budget End
2020-02-28
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611