Motor neuron disease also referred as Amyotrophic lateral sclerosis (ALS) is a rapidly progressive debilitating disease affecting upper and lower motor neurons with a median survival rate of 2-3 years. Currently, riluzole that extends survival by only 2-3 months, is the only globally approved drug. The well studied ALS genes include TDP-43, an RNA-binding protein localised within nucleus that regulate splicing and RNA metabolism.

Parkinson’s disease (PD) is a movement disorder that is now the fastest growing neurological disorder in the world. Despite much research the disease is incurable and there are no treatments that can slow the disease down. The discovery of genetic mutations in rare familial forms has transformed our understanding of the origins of PD but the function of these genes is poorly understood. Mutations in PTEN-induced kinase 1 (PINK1) cause autosomal recessive PD.

Research Overview

Parkinson’s disease (PD) is a devastating neurodegenerative condition that affects up to 10 million people worldwide and there is no cure. The overarching aim of the Sammler Group is to define biological markers and elucidate the underlying mechanisms of PD using predominantly human biological samples.

The Rousseau lab is interested in decoding how protein degradation by the proteasome is regulated in cells so that accumulation of unfolded, misfolded, or damaged proteins can be cleared before they become deleterious. The proteasome recognises, unfolds, and degrades faulty proteins that have been tagged with ubiquitin to maintain the integrity of the proteome. Defects in the proteasome give rise to various human diseases, such as cancer and neurodegenerative disorders.

The covalent attachment of the small protein ubiquitin to substrates regulates virtually all cellular processes and its modulation with small molecules is set to revolutionise modern medicine. Central players of the ubiquitin system are E3 ligase enzymes, which catalyse the covalent transfer of ubiquitin to specific substrates.

The goal of our lab is to understand how signal transduction is disrupted to cause intellectual disability, which is a major healthcare challenge world-wide. Recent data indicates that genes encoding signalling enzymes such as protein kinases are frequently mutated in intellectual disability, suggesting that these components may form novel signalling pathways which are required for neurological functioning and are disrupted in patients (1).

Intraepithelial T lymphocytes (IEL) are at the forefront of mucosal immunity - the first immune cells that pathogens and symbionts encounter in the gut. IEL are central to the protection of the gut against infection and dietary stress, but dysregulated IEL responses are also associated with autoimmune inflammatory bowel diseases such as Coeliac and Crohn’s disease. Importantly, these unique T cells reside between nutrient-absorptive intestinal epithelial cells, close to the anaerobic microbes in the intestinal lumen.

The Ganley lab is interested in unravelling the molecular mechanism of autophagy (which literally translates from the Greek meaning to eat oneself). Autophagy is a critical lysosomal degradation pathway that functions to clear the cell of potentially damaging agents, such as protein aggregates or faulty mitochondria. Importantly, autophagy appears to be dysregulated in many diseases and therefore its modulation could lead to novel therapies. However, to enable this, we first need to understand the machinery involved.

Autophagy is a lysosomal degradation pathway that is activated upon stress to facilitate clearance of damaged/toxic intracellular contents and recycle essential building blocks to sustain cell survival. The Liang Lab has a particular interest in understanding the physiological roles and pathological impacts of endoplasmic reticulum-specific autophagy (ER-phagy). We previously performed genome-wide CRISPR/Cas9 screens and uncovered many novel players that regulate ER-phagy (Liang and Corn, 2022).

There is great need for improved understanding of the mechanistic biology underlying Parkinson’s disease. Such knowledge will help with development of new drugs that slow or even halt the progression of the disease. The discovery that hyper-activating mutations in a protein kinase termed LRRK2 causes Parkinson’s, offers the prospect of elaborating new, potentially disease-modifying treatments (1, 2).