Deciphering pathomechanisms of ALS through the lens of axonal biology

Host: Dario Alessi

Venue: MSI Small Lecture Theatre, SLS

Abstract:

Amyotrophic Lateral Sclerosis (ALS) is a neuromuscular disorder characterized by the selective demise of motor neurons (MNs), leading to the paralysis and death of patients within 3-5 years after diagnosis. MNs reside in the spinal cord and possess incredibly long axons, which project to the muscle to control movement. Dysregulation of MN axons (e.g. defects in transport, local translation, cytoskeletal maintenance) is a key contributor to MN death during ALS.

In my talk, I will discuss data on how the neurotrophic factor, brain-derived neurotrophic factor (BDNF), acts as a core regulator of axonal homeostasis in human iPSC-derived MNs. Using bioengineered compartmentalized cultures, we reveal the axonal-specific kinase pathways governed by BDNF that control axonal regeneration and organelle transport. Phosphoproteomics reveal that BDNF governs altered phosphorylation state of cytoskeletal-binding proteins in human motor neurons. Additionally, using metabolic labelling with RNA-sequencing, we reveal that BDNF activates transcription factors and gene-regulatory networks that strikingly overlap with those that promote axonal regeneration of peripheral neurons. These data point towards BDNF as a therapeutic target for counteracting axonal degeneration in ALS.

 I will also briefly touch on my on-going and unpublished work on the crosstalk between the RNA-binding protein, TDP-43, and RNA methylation - specifically how this interaction may contribute to axonal degeneration during ALS. N6-methyladosine (m6A), the most abundant RNA methylation event in the brain, controls the metabolism and localization of mRNAs into axons. Recent work suggests that TDP-43 binds methylated RNA and that m6A levels are perturbed in ALS human spinal cord MNs. Thus, dissecting the interplay between TDP-43 and m6A-ylation on RNA metabolism may reveal how motor neurons perish selectively during ALS.

 Bio:

Dr. Jobert Vargas is a Miriam Mark Research Fellow in Neurodegeneration (Brain Research, UK) and a Target ALS Springboard Postdoctoral Fellow. He is hosted within the Dept. of Neuromuscular Diseases, Queen Square Institute of Neurology UCL, under the mentorship of Prof. Giampietro Schiavo, as well as Prof. Pietro Fratta. His current work broadly explores how axon-specific molecular events in human MNs confer resilience or susceptibility towards ALS pathology. In addition to his independent Fellowships, Jobert has received funding for his work from the UK DRI and Rosetrees Foundation.

 For his PhD, Jobert was a Fellow of the highly selective NIH-UCL Joint Neuroscience Program. His PhD work focused on mitophagy mechanisms, which he performed in the laboratory of Dr. Richard Youle at the NIH (co-mentored by Prof. Schiavo.) His thesis work utilized CRISPR KO lines and chemically-inducible dimerization assays to reveal that the selective autophagy receptor NDP52 associates with FIP200/ULK1 to initiate autophagosome biogenesis on directly damaged mitochondria. This work, along with the work of others, led to development of strategies using multi-specific compounds that mimic receptor proteins to target toxic cellular components for autophagic degradation.