Kenneth Matt Scaglione, PhD
Department of Molecular Genetics and Microbiology
Center for Neurodegeneration and Neurotherapeutics
Maintenance of protein homeostasis (proteostasis) is critical for cell survival. In many neurodegenerative diseases the loss of proteostasis is thought to be one of the underlying causes of neuronal loss. To counteract disruptions in proteostasis cells encode a number of molecular chaperones and ubiquitination enzymes that function to either refold or degrade misfolded proteins. Research in my laboratory focuses on understanding how these pathways play a protective role in neurodegenerative diseases. Below is an outline of major research programs in the lab.
1) Proteostasis in Dictyostelium discoideum
The polyglutamine diseases are a group of nine neurodegenerative diseases cause by expansion of a polyglutamine (polyQ) tract in the coding region of specific genes. PolyQ expansion causes these proteins to misfold and aggregate, and these protein aggregates are thought to drive neuronal death. Unlike other sequenced genomes the social amoeba Dictyostelium discoideum normally encodes massive amounts of polyglutamine repeats and many of these repeats reach the pathogenic range. Work from our group and others has demonstrated that unlike other model organisms Dictyostelium is naturally resistant to polyQ aggregation (Santarriaga et al, J Biol, Chem 2015; Malinovska L et al, PNAS, 2015). Further work from our group has identified a novel molecular chaperone we named serine-rich chaperone protein 1 (SRCP1) that is both necessary for Dictyostelium’s resistance to polyQ aggregation and sufficient to impart resistance to other organisms (Santarriaga et al, Mol Cell, 2018). Ongoing work in the lab is focused on answering these questions:
- What is the mechanism SRCP1 utilizes to suppress polyQ aggregation?
- Can SRCP1 suppress aggregation of proteins implicated in other neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and ALS?
- Does SRCP1 have beneficial effects in mouse models of neurodegenerative diseases?
- What is the function of the other SRCP1 like proteins encoded in Dictyostelium’s genome?
2) Development of small molecule regulators of the E3 ligase CHIP
C-terminus of Hsc70 Interacting Protein (CHIP) is an important E3 ligase that sits at the interface of protein folding and protein degradation. CHIP recruits molecular chaperones via a N-terminal tetratricopeptide repeat domain, and recruits E2 ubiquitin conjugating enzymes via a C-terminal U-box domain. Together these domains bring chaperone-bound client proteins into close proximity with E2 ubiquitin conjugating enzymes to facilitate ubiquitination of misfolded proteins. In vivo CHIP plays an important neuroprotective role and mutations in CHIP cause a rare neurodegenerative disease called Spinocerebellar ataxia autosomal recessive 16 (SCAR16). Our lab has found that the mutations in CHIP that cause SCAR16 do so mostly by destabilizing CHIP (Kanack et al, J Biol Chem, 2018). Using this information, we have established a high throughput screening method to identify small molecules that alter CHIP activity. Currently we are investigating lead molecules to determine if they may be useful for treating neurodegenerative diseases.
3) Investigation of Ube2w, a novel E2 ubiquitin conjugating enzyme
Ubiquitin conjugating enzymes (E2’s) typically attach ubiquitin to lysine residues on their substrates. Unlike other E2’s Ube2w conjugates ubiquitin to the alpha amino terminus of proteins and not to internal lysine residues (Scaglione et al, J Biol Chem, 2013; Tatham et al, Biochem, 2013). Despite this novel biochemical property of Ube2w little is known about Ube2w’s physiological function. We are currently employing genome and proteome wide approaches to understand the physiological function of Ube2w and N-terminal ubiquitination.