Pharmacologic Targeting of the C-Terminus of Heat Shock Protein 90 Improves Neuromuscular Function in Animal Models of Charcot Marie Tooth X1 Disease.

Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Cemdomespib is an orally bioavailable novologue that manifests neuroprotective activity by modulating the expression of heat shock protein 70 (Hsp70).

Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons.

Diabetic peripheral neuropathy (DPN) is a complication of diabetes whose pathophysiology is linked to altered mitochondrial bioenergetics (mtBE). KU-596 is a small molecule neurotherapeutic that reverses symptoms of DPN, improves sensory neuron mtBE, and decreases the pro-oxidant protein, thioredoxin-interacting protein (Txnip) in a heat shock protein 70 (Hsp70)-dependent manner. However, the mechanism by which KU-596 improves mtBE and the role of Txnip in drug efficacy remains unknown.

Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice.

Mitochondria damage plays a critical role in acetaminophen (APAP)-induced necrosis and liver injury. Cells can adapt and protect themselves by removing damaged mitochondria via mitophagy. PINK1-Parkin pathway is one of the major pathways that regulate mitophagy but its role in APAP-induced liver injury is still elusive.