Protein accumulation is a soundly documented feature of all age-related neurodegenerative disorders, however the initiating events that lead to their formation, as well as their relationship to disease, remains unknown. Parkinson's disease (PD) is characterized by the conversion of a normally soluble synaptic protein called a-synuclein into insoluble amyloid fibrils that comprise Lewy body inclusions within Parkinson's brain. Our recent data indicated that disruption of cellular degradation capacity through mutations in the lysosomal gene GBA1 contribute to the aggregation of a-synuclein. This suggested that disruption of lysosomal function contributes to the formation of Lewy bodies. Interestingly, we found that when a-synuclein accumulates, it can in turn feedback to inhibit the lysosomal system, thus causing a self-propagating cycle that promotes amyloid formation and growth within neurons. Our preliminary data indicate that a-synuclein inhibits the trafficking of hydrolases and prevents them from reaching the lysosomal compartment; however the molecular mechanism is not known. Experiments outlined in this application aim to delineate how a-syn disrupts lysosomes using cell lines, PD patient-derived induced pluripotent stem cell models, transgenic mice, and PD brain. Our goals are to 1) define the relationship between distinct a-syn aggregated assemblies and lysosomal dysfunction / neurotoxicity, 2) determine how a-syn affects protein trafficking of lysosomal hydrolases, 3) discover new rescue pathways in PD centered around promoting hydrolase folding and trafficking to the lysosome. These studies will provide new insight into the mechanism of how amyloid aggregates disrupt cellular processes, and identify novel therapeutic pathways for synucleinopathies centered on enhancement of the lysosomal clearance pathway.

Public Health Relevance

Protein aggregates are found in all age-related neurodegenerative diseases, however the relationship of the aggregation process to cellular toxicity is not understood. This proposal aims to elucidate pathogenic cellular pathways responsible for promoting the formation of aggregates and define the downstream toxic action within cells. Our studies will advance our understanding of how neurons die in these diseases, and identify new cellular pathways for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092823-05
Application #
9751407
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Cheever, Thomas
Project Start
2015-08-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
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
Zunke, Friederike; Moise, Alexandra C; Belur, Nandkishore R et al. (2018) Reversible Conformational Conversion of ?-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron 97:92-107.e10
Stojkovska, Iva; Krainc, Dimitri; Mazzulli, Joseph R (2018) Molecular mechanisms of ?-synuclein and GBA1 in Parkinson's disease. Cell Tissue Res 373:51-60
Klein, Andrés D; Mazzulli, Joseph R (2018) Is Parkinson's disease a lysosomal disorder? Brain :
Pitcairn, Caleb; Wani, Willayat Yousuf; Mazzulli, Joseph R (2018) Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease. Neurobiol Dis :
Burbulla, Lena F; Song, Pingping; Mazzulli, Joseph R et al. (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357:1255-1261
Mor, Danielle E; Tsika, Elpida; Mazzulli, Joseph R et al. (2017) Dopamine induces soluble ?-synuclein oligomers and nigrostriatal degeneration. Nat Neurosci 20:1560-1568
Mazzulli, Joseph R; Zunke, Friederike; Tsunemi, Taiji et al. (2016) Activation of ?-Glucocerebrosidase Reduces Pathological ?-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons. J Neurosci 36:7693-706
Zunke, Friederike; Andresen, Lisa; Wesseler, Sophia et al. (2016) Characterization of the complex formed by ?-glucocerebrosidase and the lysosomal integral membrane protein type-2. Proc Natl Acad Sci U S A 113:3791-6
Chung, Sun Young; Kishinevsky, Sarah; Mazzulli, Joseph R et al. (2016) Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and ?-Synuclein Accumulation. Stem Cell Reports 7:664-677
Mazzulli, Joseph R; Zunke, Friederike; Isacson, Ole et al. (2016) ?-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc Natl Acad Sci U S A 113:1931-6

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