Amyotrophic lateral sclerosis (ALS)—the commonest type of motor neuron disease (MND)—is a rapidly progressive paralysing illness of mid-adulthood. It has a lifetime risk of ~1 in 400, resulting from the selective neurodegeneration of upper and lower motor neurons (MNs). ~10% of ALS is inherited, and the rest occurs spontaneously. The median survival from symptom onset is 3 years and there are no significant treatments, and no cure. The only globally licensed medication, Riluzole, prolongs survival by a few months on average, and was introduced in the mid 1990s.

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.

Parkinson’s disease (PD) is the fastest growing neurodegenerative disorder worldwide, but its underlying biology is complex and heterogeneous. While targeted treatments are beginning to emerge, there remains an urgent need to stratify patients into biological subgroups to ensure that disease-modifying therapies can be delivered to the right people at the right time. Biomarkers that define these subgroups are therefore central to the future of precision medicine in PD.

The Rousseau lab is dedicated to decoding how proteasome-mediated protein degradation is regulated in cells to prevent the harmful accumulation of unfolded, misfolded, or damaged proteins. The proteasome recognises, unfolds, and degrades proteins tagged with ubiquitin, thereby safeguarding proteome integrity. By degrading 80–90% of intracellular proteins, the proteasome is a central hub of the protein homeostasis network, preventing the toxic buildup of protein aggregates that can impair cellular function.

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).

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.

Approximately one third of the human proteome depends on the endoplasmic reticulum (ER) for its biosynthesis. During translation, ribosomes can sometimes stall, triggering a chain of events that results in the decay of defective mRNAs, recycling of stalled ribosomes and crucially, degradation of partially synthesized nascent polypeptides. UFM1 is an enigmatic ubiquitin-like modifier that is attached to ER-associated ribosomes when stalling occurs.

The endoplasmic reticulum (ER) plays a central role in protein folding, modification, and secretion. Perturbations in these processes trigger ER stress and activate the unfolded protein response (UPR), a signaling network that aims to restore ER homeostasis. Dysregulation of ER homeostasis contributes to a wide range of pathologies, including cancer, tissue fibrosis, metabolic disorders, and neurodevelopmental defects. ER quality control is also maintained by the proteasome (via ER-associated degradation, ERAD) and the autolysosome (via ER-specific autophagy, ER-phagy)^1-3.

The challenge

Mutations in the kinase LRRK2 are one of the most common inherited causes of Parkinson’s disease, yet we still don’t fully understand how LRRK2 drives disease at the molecular level (1, 2). Our lab aims to change that, by uncovering how LRRK2 signalling is regulated, how it malfunctions in Parkinson’s disease, and how these insights can guide the discovery of new biomarkers and therapeutic targets.

The discovery