Maios, C. | bioRxiv Science

bioRxiv2023

Protein Assembly Modulation: A New Approach to ALS Therapeutics

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with a complex, multifactorial pathophysiology, most commonly manifest as loss of motor neurons. We introduce a new mechanism of ALS pathogenesis via a novel drug-like small molecule series that targets protein disulfide isomerase (PDI) within a previously unappreciated transient and energy-dependent multi-protein complex. This novel drug was found to have activity in cellular models for both familial and sporadic ALS, as well as in transgenic worms, flies, and mice bearing a diversity of human genes with ALS-associated mutations. These compounds were initially identified as modulators of human immunodeficiency virus (HIV) capsid assembly in cell-free protein synthesis and assembly (CFPSA) systems, with demonstrated antiviral activity in cell culture. Their advancement as ALS-therapeutics, and the subsequent separation of activity against HIV and ALS in chemical subseries through structure-activity-relationship optimization, may provide insights into the molecular mechanisms governing pathophysiology of disordered homeostasis relevant to ALS.

neuroscience↗

bioRxiv2023

Mimicking of tau hyperphosphorylation in GABAergic motoneurons of C. elegans induces severe peripheral and neuronal alterations

In several neurodegenerative diseases including Alzheimers disease (AD), tau, a microtubule-associated protein (MAP) enriched in the axon, becomes hyperphosphorylated, detaches from microtubules, redistributes to the somato-dendritic compartment and self-aggregates. The mechanisms leading to neuronal dysfunction and death by tau pathology remain to be fully elucidated. C. elegans has been successfully used by several groups including ours to identify mechanisms involved in neurodegeneration. We generated three strains, one overexpressing wild-type human tau (WT Tau), one a tau mutant mimicking hyperphosphorylation (hyperP Tau) and one preventing phosphorylation (hypoP Tau) in GABA motor neurons. A significant reduction of body size and egg laying was noted in these tau strains. Starting at day 1, we found that the worms overexpressing hyperP Tau were smaller than the N2 control strain and the worms either overexpressing WT Tau or hypoP Tau. Starting at day 5, the worms overexpressing WT Tau were smaller than control and the worms overexpressing hypoP Tau. Egg laying was reduced in both hyperP Tau and WT Tau worms. Survival was only decreased in WT Tau worms. Motility deficits were also observed. For age-dependent paralysis, a difference was noted between control and hyperP Tau. Swimming activity and speed were increased in hypoP Tau and decreased in hyperP Tau strains. Axonal integrity was altered in all tau strains. In the case of synaptic activity, at day 1, it was increased in the hypoP Tau strain and decreased in the hyperP Tau one. Collectively, our data revealed that overexpression of tau exerted neuronal and peripheral defects indicating that tau dysfunction could affect cell-cell communication.

neuroscience↗