A5062717814- Endoplasmic Reticulum Stress and Disease
- Lysosomal Storage Disorders Research
- Heat shock proteins research
- Cellular transport and secretion
- Mitochondrial Function and Pathology
- Genetics, Aging, and Longevity in Model Organisms
- Aging and Gerontology Research
- Spaceflight effects on biology
- Calpain Protease Function and Regulation
- Glycogen Storage Diseases and Myoclonus
- Protein Structure and Dynamics
- RNA Research and Splicing
- GABA and Rice Research
- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Nostalgia and Consumer Behavior
University of Pennsylvania
2021-2024
Yale University
2017-2022
Loss-of-function mutations in the depalmitoylating enzyme palmitoyl protein thioesterase 1 (PPT1) cause neuronal ceroid lipofuscinosis (NCL), a devastating neurodegenerative disease. The substrates of PPT1 are largely undescribed, posing limitation on molecular dissection disease mechanisms and therapeutic development. Here, we provide resource identifying >100 novel substrates. We utilized Acyl Resin-Assisted Capture (Acyl RAC) mass spectrometry to identify proteins with increased vivo...
Parkinson's disease is characterized by the aggregation of presynaptic protein α-synuclein and its deposition into pathologic Lewy bodies. While extensive research has been carried out on mediators aggregation, molecular facilitators disaggregation are still generally unknown. We investigated role chaperones in both preventing disaggregating oligomers fibrils, with a focus mammalian disaggregase complex. Here, we show that overexpression chaperone Hsp110 sufficient to reduce cell culture...
Abstract Hsp70, Hsp40, and Hsp110 form a human protein-disaggregase system that solubilizes reactivates proteins trapped in aggregated states. However, this fails to maintain proteostasis fatal neurodegenerative diseases. Here, we potentiate the Hsp70-disaggregase pharmacologically. By scouring collection of dihydropyrimidines, disambiguate small molecule specifically stimulates against disordered aggregates α-synuclein fibrils. The newly identified lead compound disaggregase activity...
SUMMARY Loss-of-function mutations in the depalmitoylating enzyme palmitoyl protein thioesterase 1 (PPT1) cause Neuronal Ceroid Lipofuscinosis type ( CLN1 ), a devastating neurodegenerative disease. Here, we provide resource identifying PPT1 substrates. We utilized Acyl Resin-Assisted Capture and mass spectrometry to identify proteins with increased vivo palmitoylation knockout mouse brains. then validated putative substrates through direct depalmitoylation recombinant PPT1. This stringent...
Toxic and pathologic protein aggregation is a common feature of neurodegenerative diseases from Alzheimer's Parkinson's to amyotrophic lateral sclerosis (ALS). Chaperone proteins such as the metazoan heat shock 70 (Hsp70), Hsp40, Hsp110 complex can identify these misfolded aggregates restore them their functional native states. However, previous studies have used wide range chaperone components proportions. Using aggregated firefly luciferase model substrate, we set out optimize...