Title: Cell-autonomous and non-cell-autonomous effects of TRIM72 on ALS disease progression

Abstract Dysfunction of RNA-binding proteins, including TDP-43 and FUS, has been associated with amyotrophic lateral sclerosis (ALS); however, the underlying mechanisms are largely unknown. Here, we reported that a neuronal upregulation of TRIM72 (Tripartite Motif Containing 72) in FUS mutation knockin ALS models slows disease progression. TRIM72 interacts with Commander, a protein complex for recycling of membrane proteins, facilitating membrane repair and antioxidation. Exosomal TRIM72 is detected in ALS patient cerebrospinal fluid (CSF) and extracellular application of exosomal TRIM72 protects cell from membrane damage. In a sporadic ALS cohort, CSF TRIM72 level associates ALS disease progression. AAV-mediated neuronal expression of TRIM72 slows down the disease progressions in ALS models and in an ALS patient without adverse effects over a year treatment course. Taken together, our results suggest a universal neuronal protection of a TRIM family protein in cell-autonomous and non-cell-autonomous manners in ALS.