Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, Maryland 20814
Office Phone: (301) 295-3506
Lab Phone: (301) 295-3819
Proteolysis via the ubiquitin proteasome system (UPS) is a tightly regulated, rapid and effective mechanism for degrading specific proteins. Protein substrates are targeted for degradation by the proteasome through addition of a chain of ubiquitins. Ubiquitin conjugation is accomplished in sequential reactions, catalyzed by a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3). Attachment of a chain of 4 or more ubiquitins targets a protein for degradation by the proteasome. A single E1 enzyme transfers ubiquitin to all the E2s in the cell, and a small repertoire of E2s directly transfers ubiquitin to either an E3 or to a lysine residue on the substrate. The E3s are primarily responsible for conferring substrate specificity.
Many neurodegenerative diseases result from insufficient levels of essential proteins or a buildup of toxic ones. These neurodegenerative diseases include disorders in which the pathological proteins may accumulate as is the case with polyglutamine expansion disease proteins, α-synuclein in Parkinson's disease, and tau and amyloid-β (Aβ) in Alzheimer's disease or diseases resulting from deficiency of essential proteins as in spinal muscular atrophy and muscular dystrophy. Understanding the molecular basis of protein degradation and developing strategies to manipulate these processes is thus important in developing treatments for a myriad of diseases.
A fundamental question with relevance to many neurodegenerative diseases is how disease proteins are targeted for degradation. Research in this area has been limited by the fact that (i) most of the current compounds target the catalytic sites of the proteasome and have significant associated toxicity whilst only a few target the enzymes that selectively tag a protein for degradation (ii) many compounds that target the UPS, when given systemically, do not enter the central nervous system (CNS) in appreciable levels, and (iii) the role of the UPS in the development and maintenance of neurons is not very well understood.
Our goal is to begin answering some of these outstanding questions using genetic and biochemical techniques.