Dissertation Defense - Ahmed Malik

Award Date

Monday, March 22, 2021

Recipient

Matrin 3 Regulation in Physiology and Neurodegenerative Disease

Dr. Sami Barmada, Chair

RNA-binding proteins (RBPs) are critical for the regulation of RNA splicing, transport, and translation. Over the previous decade, evidence has accumulated linking RBP dysfunction to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorders, with mutations in the genes encoding many RBPs resulting in inherited disease and RBP pathology observed even in sporadic disease. Mutations in the gene encoding Matrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, have been implicated in ALS, ALS/FTD, and a form of distal myopathy, and MATR3 pathology is also seen in patients with sporadic ALS. Despite this, little is known about MATR3 function and physiological regulation or about the pathophysiological processes underlying MATR3-mediated neurodegeneration.

In this dissertation defense, I will present findings on basic MATR3 biology, including determinants of its abundance and distribution in neurons, as well as on pathological mechanisms as they relate to disease-associated MATR3 mutations. Using a primary cortical neuron model, we found that neurons are bidirectionally vulnerable to changes in MATR3 levels and that RNA binding by MATR3 antagonizes its phase separation into liquid-like droplets, placing it squarely within a broader group of ALS/FTD-linked RBPs. In investigating the determinations of MATR3 abundance, we uncovered an NMDAR-, Ca2+-, and calpain-dependent mechanism of MATR3 degradation after neuronal activity that is impaired by the most common pathogenic mutation. Furthermore, parallel studies of MATR3 regulation by Ca2+ signaling revealed an interaction with Ca2+-bound calmodulin that inhibits the ability of MATR3 to effectively bind RNA, and this dynamic, activity-dependent mechanism for tuning RBP function may extend to many other ALS/FTD-linked RBPs as well.

This work offers a foundation for understanding not only the fundamental biology of MATR3 in neurons but also the pathological processes underlying MATR3-mediated disorders. It is our hope that these insights on neuronal regulation of MATR3 will inform future studies on activity-mediated RBP control and will further our knowledge of neurological disease linked to RBP dysfunction.