# Isolating small-molecule enhancers of the human alpha-synuclein disaggregase machinery

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2020 · $240,441

## Abstract

Project summary
In Parkinson's Disease (PD), the most common neurodegenerative movement disorder that afflicts millions of
people worldwide, the proteostasis network breaks down and fails to counter the misfolding of the small
presynaptic protein α-synuclein (α-syn). α-Syn populates a range of misfolded structures ranging from soluble
toxic oligomers to self-templating amyloid fibrils capable of initiating and propagating disease de novo. α-Syn
fibrils cluster into large cytoplasmic inclusions termed Lewy Bodies, a pathological hallmark of PD. Recently,
we and others have discovered a series of human molecular chaperones, Hsp110, Hsp70, Hsp40, and HspB5
which can disaggregate α-syn fibrils and reduce their toxicity. Whether this system can also disassemble toxic
soluble α-syn oligomers remains unclear. This endogenous disaggregase system likely becomes overwhelmed
and fails to counter α-syn misfolding in PD and related α-synucleinopathies. Indeed, Hsp70 chaperones are
often sequestered and depleted by excessive accumulation of misfolded proteins. Methods to stimulate the
Hsp110, Hsp70, Hsp40, and HspB5 disaggregase machinery in the degenerating neurons of PD patients could
reverse deleterious accumulation of α-syn and provide a game-changing solution for PD. Thus, we propose
that the Hsp110, Hsp70, Hsp40, and HspB5 disaggregase machinery represents a promising, novel PD-
relevant target. We hypothesize that enhancing the activity of the Hsp110, Hsp70, Hsp40, and HspB5
disaggregase system with specific brain-penetrant small molecules will enable dissolution of toxic
oligomeric and amyloid forms of α-syn, and confer therapeutic benefits in PD. In the proposed studies,
we will pursue two specific aims: (1) isolate brain-penetrant small molecules that enhance the ability of Hsp110,
Hsp70, Hsp40, and HspB5 to disaggregate α-syn oligomers and fibrils; and (2) Determine the ability of brain-
penetrant, small-molecule enhancers of Hsp110, Hsp70, Hsp40, and HspB5 disaggregase activity to mitigate
α-syn misfolding and toxicity in primary neurons. This project makes an important first step toward exploring
the feasibility of developing brain-penetrant small-molecule therapeutics that enhance the activity of the human
α-syn disaggregase machinery (Hsp110, Hsp70, Hsp40, and HspB5) as an alternative treatment strategy for
PD. By the end of our studies, there will be a clear “go/no go” decision for moving a brain-penetrant small-
molecule enhancer of Hsp110, Hsp70, Hsp40, and HspB5 disaggregase activity into rodent models and
ultimately PD patients. Small-molecule stimulation of the human protein-disaggregase machinery could reverse
deleterious α-syn misfolding in degenerating dopaminergic neurons and provide a transformative solution for
PD and related α-synucleinopathies including dementia with Lewy Bodies and multisystem atrophy.
Importantly, brain-penetrant small-molecule enhancers of Hsp110, Hsp70, Hsp40, and HspB5 may also have
important applications in o...

## Key facts

- **NIH application ID:** 9851778
- **Project number:** 5R21AG061784-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** James Shorter
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $240,441
- **Award type:** 5
- **Project period:** 2019-02-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851778

## Citation

> US National Institutes of Health, RePORTER application 9851778, Isolating small-molecule enhancers of the human alpha-synuclein disaggregase machinery (5R21AG061784-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851778. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*