Arthur L Horwich MD
Sterling Professor of Genetics and Professor of Pediatrics; Investigator HHMI
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 as caused by protein misfolding, seeking to understand how misfolded SOD1 enzyme in the cytosol of motor neurons leads to one form of ALS. His lab is modeling mutant SOD1-linked ALS in mice transgenic for a mutant SOD1-YFP, the YFP moiety offering a fluorescent reporter of the mutant protein and “tag” for biochemical studies. The transgenic mutant strain presents YFP fluorescent aggregates in motor neurons by the time of weaning, develops muscle weakness, and paralyzes by 6 months of age. 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 cord remains free of aggregates. The nature of injury to the motor system of the mutant mice is under study, particularly at the level of lower motor neurons, examining their dendritic arbors, cell bodies, axons, and neuromuscular junctions, using both morphologic and electrophysiologic approaches. What is the most immediate target of the misfolded protein, and at what level in the motor system? Notably, endogenous molecular chaperones, Hsc70 and Hsp110, associate with the misfolded protein – they are obviously not able to fully protect the system. Can their overexpression alter the progression of motor dysfunction?