Arthur Horwich, MD

Horwich received undergraduate and M.D. degrees from Brown University, trained in Pediatrics at Yale, was then a postdoctoral fellow first at Salk Institute in the Tumor Virology Laboratory, and then in Genetics at Yale, then joined the Yale faculty. His work was initially involved with protein import into mitochondria and resulted in discovery of a "folding machine" inside mitochondria, Hsp60. He has used genetic, biochemical, and biophysical tools to study the mechanism of action of these ring shaped so-called chaperonin machines that provide essential assistance to protein folding in many cellular compartments. More recently he has focused on neurodegenerative disease, modeling mutant SOD1-linked ALS in mice transgenic for a mutant SOD1 fused with a YFP reporter. In the transgenic mutant strain, the mutant SOD1 misfolds and lodges the fusion protein in YFP fluorescent aggregates, visible in motor neurons by 2-3 months of age. These neurons are removed by microglial cells, associated with loss of ~50% of motor neurons. By 6-7 months of age the mice exhibit lower extremity paralysis, associated with loss of ~50% of the remaining motor neurons. By contrast, a wtSOD1-YFP transgenic strain with the same amount of total SOD1-YFP protein in spinal cord remains asymptomatic even after two years, and the spinal cord remains free of aggregates. An early study showed that overexpression of the molecular chaperone Hsp110, known to be part of a chaperone disaggregase, improved survival of the SOD1-YFP mice. Additional genetic modifiers are being tested.