Opposing roles of p38alpha-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.
Publication Year:
2025
PubMed ID:
39817908
Funding Grants:
Public Summary:
Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes motor neurons, the nerve cells that control movement, to die. A key feature of ALS is the buildup of abnormal clumps of a protein called TDP-43 inside these neurons. Scientists do not yet fully understand how these clumps form or why they are toxic. In this study, we discovered that an enzyme called p38α MAPK drives harmful changes to TDP-43. When this enzyme is overactive, it adds phosphate groups to TDP-43, a chemical change known as phosphorylation. This modification causes TDP-43 to misfold, form clumps, and move out of the nucleus into the cytoplasm, which mirrors what happens in ALS. Blocking p38α MAPK prevented these damaging changes and protected nerve cells, including those derived from ALS patients. We also found that another enzyme, PRMT1, adds methyl groups to TDP-43 in a nearby region. This modification has the opposite effect: it helps TDP-43 stay soluble and reduces toxic aggregation. Interestingly, the two chemical changes compete with each other. When p38α MAPK adds phosphate groups, PRMT1 methylation decreases, which promotes aggregation. These results reveal a delicate molecular balance that determines whether TDP-43 remains healthy or becomes harmful. Targeting this pathway by blocking p38α MAPK or enhancing PRMT1 activity could open new paths for treating ALS and other diseases involving TDP-43 buildup.
Scientific Abstract:
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38alpha MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38alpha MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38alpha MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38alpha-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.
