The synucleinopathies, including Dementia with Lewy bodies (DLB), Multiple system atrophy (MSA), and Parkinson's disease (PD), are a group of neurodegenerative disorders characterized by the accumulation of alpha-synuclein (a-syn), a small neural- specific protein that aberrantly aggregates into amyloid fibrils that comprise Lewy bodies, the characteristic pathological inclusions found in synucleinopathies. One of the critical issues in PD research, as well as across several neurodegenerative disease research areas, is how to target the specific toxic, pathogenic moiety for therapeutic development. The in vivo processes and cellular factors that control the formation of a-syn toxic forms are largely unknown. The recent discovery of parkinsonism and Lewy bodies in patients with Gaucher disease (GD), a rare lysosomal storage disorder characterized by mutations in the gene (GBA1) encoding glucocerebrosidase (GC)ase, suggests a link between lysosomal sphingolipid metabolism and a-syn aggregation. In our preliminary data we show that depletion of GCase results in endogenous a-syn accumulation and neurodegeneration in mouse and C. elegans models of GD. Compromised GCase activity in neurons led to accumulation of the GCase substrate glucosylceramide, diminished lysosomal function, and increased soluble a-syn oligomeric intermediates that were neurotoxic. Importantly, we found that a-syn accumulation has the ability to affect the lysosomal maturation and activity of normal GCase in neurons and human brain, suggesting that GlcCer accumulation also plays a role in sporadic PD and other synucleinopathies. The experiments proposed in this application will further test the hypothesis that alterations in GlcCer metabolism contribute to the pathogenesis of synucleinopathies. We will examine whether therapeutic targeting of mutated or normal glucocerebrosidase to lysosomes prevents or diminishes formation of toxic alpha- synuclein oligomers and breaks the vicious cycle of alpha-synuclein aggregation and toxicity. If successful, these studies will provide further validation for a role of lysosomal GCase in synucleinopathies and identify a specific molecular pathway for the development of new therapies for PD and related diseases characterized by accumulation of a-syn.

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We propose to develop strategies to facilitate clearance of accumulated alpha-alpha- synuclein by targeting lysosomal enzyme glucocerebrosidase that is mutated in Gaucher disease (GD). Since clinical and genetic links between GD and parkinsonism have been established, our approach, if successful, should provide a specific molecular target for therapeutic development in parkinsonism and other synucleinopathies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sutherland, Margaret L
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Massachusetts General Hospital
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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
Conrad, Karen S; Cheng, Ting-Wen; Ysselstein, Daniel et al. (2017) Lysosomal integral membrane protein-2 as a phospholipid receptor revealed by biophysical and cellular studies. Nat Commun 8:1908
Stojkovska, Iva; Krainc, Dimitri; Mazzulli, Joseph R (2017) Molecular mechanisms of ?-synuclein and GBA1 in Parkinson's disease. Cell Tissue Res :
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
Burbulla, Lena F; Beaumont, Kristin G; Mrksich, Milan et al. (2016) Micropatterning Facilitates the Long-Term Growth and Analysis of iPSC-Derived Individual Human Neurons and Neuronal Networks. Adv Healthc Mater 5:1894-903
Zheng, Jianbin; Chen, Long; Schwake, Michael et al. (2016) Design and Synthesis of Potent Quinazolines as Selective ?-Glucocerebrosidase Modulators. J Med Chem 59:8508-20
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
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
Song, Pingping; Trajkovic, Katarina; Tsunemi, Taiji et al. (2016) Parkin Modulates Endosomal Organization and Function of the Endo-Lysosomal Pathway. J Neurosci 36:2425-37
Mazzulli, Joseph R; Burbulla, Lena F; Krainc, Dimitri et al. (2016) Detection of Free and Protein-Bound ortho-Quinones by Near-Infrared Fluorescence. Anal Chem 88:2399-405

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