FMRP ‐Mediated Proteasome Regulation: A Novel Mechanism in ALS Pathology

ABSTRACT Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the hallmark cytoplasmic accumulation and aggregation of TAR DNA binding protein 43 (TDP‐43), which impairs proteasome activity through its interaction with Tankyrase (TNKS). Using molecular and imaging techniques, we have identified a novel role for the Fragile X Mental Retardation Protein (FMRP) in regulating the TNKS/PI31‐mediated proteasome activation mechanism in co‐operation with TDP‐43. Our results demonstrate that depletion of FMRP causes nuclear translocation of TDP‐43, reducing cytoplasmic TNKS/TDP‐43 co‐localization, thereby releasing TNKS in the cytoplasm. Free TNKS gets associated with proteasome inhibitor of 31 kDa (PI31), reversing PI31‐mediated inhibition of proteasome assembly, trafficking, and activity. Thus, FMRP regulates proteasome activity by modulating the subcellular distribution of TDP‐43. Interestingly, FMRP expression is elevated in specific brain regions and spinal cords of TDP‐43 A315T transgenic ALS mice that helps more TDP‐43 to stay in cytoplasm to sequester more TNKS with it, resulting in proteasome dysfunction in ALS disease system. We have demonstrated for the first time that FMRP can act as a disease modifier for ALS. ALS patients with high FMRP expression in the brain and spinal cord may exhibit more severe protein aggregation due to proteasome dysfunction.