Burnett Lab

Cellular Proteolysis and Neurodegeneration

Overview

Proteolysis via the UPS is a tightly regulated, rapid and effective mechanism for degrading specific proteins and in many cases degradation occurs only in response to particular cellular stimuli. Protein substrates are targeted for degradation by the proteasome through the 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 26S 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.

Dysfunction of the UPS has been implicated in several neurodegenerative diseases including Huntington’s disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). There is growing interest in manipulating the degradative machinery as a therapeutic target to either promote degradation of pathological proteins or block degradation of critical proteins that are deficient. 

A fundamental question with relevance to many neurodegenerative diseases is how specific proteins are degraded in neuronal cells. 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 cell and animal models.

Brain Injury and the UPS​
Spinal muscular atrophy
​​Identify disease-causing genes
TBI involves primary and secondary events resulting in neuronal dysfunction and death. The ubiquitin proteasome system (UPS) plays a key regulatory role in many of the cellular processes that are disrupted after TBI, including antigen presentation, immune signaling and protein homeostasis.
We look to  identify novel therapeutic targets for  spinal muscular atrophy (SMA) and provide initial proof-of-concept that selectively stabilizing the SMN protein improves the SMA disease phenotype.
  
Hereditary neurological diseases are debilitating and often untreatable disorders. The genetic basis of many hereditary neurological disorders remains elusive. One of our research goals is to identify the genes and gain insights into the roles of these genes in the nervous system development and maintenance. 
We are thankful for current and previous support from: