Proteostasis Therapeutics is a biotechnology company developing small molecule modulators of the ubiquitin-proteasome system (UPS) for the treatment of neurodegenerative diseases. Founded in 2017 in San Diego, the company focuses on enhancing protein clearance through selective modulation of proteasome activity, particularly in Parkinson's disease["@protes_corp"].
The company was founded based on research showing that partial proteasome activation can enhance clearance of misfolded proteins without causing the cellular stress associated with full proteasome inhibition.
Scientific Rationale
Ubiquitin-Proteasome System in PD
The UPS is the primary pathway for targeted protein degradation in cells. In Parkinson's disease, [alpha-synuclein](/proteins/alpha-synuclein) and other proteins accumulate due to impaired proteasomal function[@proteasome_parkinsons].
Key observations:
Proteasome activity is reduced in PD patient brains
Mutations in parkin (E3 ligase) cause early-onset PD
[Alpha-synuclein](/proteins/alpha-synuclein) oligomers inhibit proteasome function
Enhancing proteasome activity can reduce toxic protein load
Therapeutic Approach
Proteostasis Therapeutics develops:
Proteasome activators: Enhance catalytic activity without overactivation
19S cap modifiers: Improve substrate processing
Ubiquitin-like modifiers: Enhance targeting to proteasome
Combination therapies: With autophagy enhancers[@chitsaz2019]
[The ubiquitin-proteasome system in Parkinson's disease pathogenesis, Nat Rev Neurosci (2022)](https://doi.org/10.1038/s41583-022-00588-3)
[Chitsaz A, et al. Proteasome modulation as therapeutic strategy in neurodegenerative diseases, J Med Chem (2019)](https://doi.org/10.1021/acs.jmedchem.9b00741)
[Schmidt M, et al. Ubiquitin-proteasome system in Parkinson's disease: a target for therapy? (2019)](https://pubmed.ncbi.nlm.nih.gov/31140456/)