In Parkinson's Disease (PD), the proteostasis network fails to counter the misfolding of ?-synuclein (?-syn). ?- Syn forms soluble toxic oligomers and self-templating amyloid fibrils that can initiate and propagate disease de novo. ?-Syn fibrils cluster into large cytoplasmic inclusions termed Lewy Bodies, a pathological hallmark of PD. Human molecular chaperones, Hsp110, Hsp70, and Hsp40 can disaggregate ?-syn fibrils and reduce their toxicity. These findings together with our advances with Hsp104 and potentiated variants suggest that ?-syn oligomers and fibrils are not intractable but can be rapidly disassembled into non-toxic forms. More recently, a second human protein disaggregase, HtrA1, has been discovered that disassembles and degrades tau and amyloid-beta fibrils. HtrA1 is a chaperone and homo-oligomeric PDZ serine protease found in the cytoplasm and extracellular space, which selectively degrades misfolded substrates while leaving folded substrates alone. Our unpublished data suggest that HtrA1 rescues ?-syn toxicity in yeast, and, disassembles and degrades ?- syn fibrils in vitro. We hypothesize that small-molecule enhancers of HtrA1 disaggregase activity could stimulate the elimination of deleterious ?-syn accumulations in the degenerating neurons of PD patients. Thus, we propose that the unanticipated protein disaggregase activity of HtrA1 represents a promising, novel PD- relevant target. We hypothesize that enhancing the activity of HtrA1 disaggregase activity with specific small molecules will enable dissolution and degradation of toxic oligomeric and amyloid forms of ?- syn, and confer therapeutic benefits in PD. Thus, we will pursue two specific aims: (1) Isolate small molecules that enhance the ?-syn disaggregase activity of HtrA1; and (2) Assess the ability of small-molecule enhancers of HtrA1 disaggregase activity to rescue ?-syn aggregation and toxicity in mammalian primary neuron models of PD. By the end of this project, there will be a clear ?go/no go? decision for moving a small- molecule enhancer of HtrA1 into rodent models and ultimately PD patients. Small-molecule stimulation of HtrA1 disaggregase activity could eliminate deleterious ?-syn misfolding in degenerating dopaminergic neurons and provide a game-changing solution for PD. Importantly, small-molecule enhancers of HtrA1 disaggregase activity may also have important applications in other neurodegenerative disorders caused by deleterious protein misfolding, including Alzheimer's disease and frontotemporal dementia.

Public Health Relevance

In Parkinson's Disease (PD), the most common neurodegenerative movement disorder, ?-synuclein (?-syn) misfolds into diverse oligomeric and fibrillar structures that selectively devastate dopaminergic neurons. Here, we will uncover drug-like small molecules that stimulate the ability of an endogenous protein disaggregase, HtrA1, to eliminate these toxic ?-syn structures, which could provide a transformative solution for PD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sutherland, Margaret L
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University of Pennsylvania
Schools of Medicine
United States
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Chuang, Edward; Hori, Acacia M; Hesketh, Christina D et al. (2018) Amyloid assembly and disassembly. J Cell Sci 131: