Altered cofactor regulation with disease-associated p97/VCP mutations

Age-associated degenerative diseases have similar pathogenic mechanisms related to defects in protein homeostasis. p97/VCP (valosin-containing protein) is essential for coordinating protein degradation and is mutated in a multisystem degenerative disease that affects the central nervous system, muscle, and bone. p97/VCP is an enzyme in the AAA ATPases (ATPases associated with diverse cellular activities) family, which takes apart ATP and uses this energy to perform pivotal functions. We found that p97/VCP cofactors control its enzymatic activity. p97/VCP disease mutants behave abnormally due to lack of appropriate control by these cofactors. Correcting the function of the disease-associated proteins may be a desirable approach to developing safe treatment for fatal degenerative diseases. The next steps are to screen and characterize large panels of compounds to identify potential drugs that may correct the malfunction.