TRAF6-Mediated Ubiquitin Signaling Drives Long-Term Neurodegeneration in a Mouse Model of Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease leading to cerebral complications. It is triggered by single or repetitive traumatic brain injury during contact sports or combat activities. Due to diagnostic limitations, i.e., being restricted to postmortem analysis, understanding of CTE remains incomplete. While acute CTE mechanisms have been studied, the long-term effects remain inadequately explored. We investigated long-term CTE mechanisms using mouse models with 3- and 6-month progression. The 6-month model showed increased neurodegeneration and upregulation of ubiquitin signaling pathway genes, identifying TRAF6 as the central node. Accordingly, TRAF6 suppression using AAV9-delivered shRNA after brain injury protected against damage and behavioral deficits. However, TRAF6 knockdown in uninjured animals induced CTE-like changes, suggesting trauma activates compensatory mechanisms. Circulating microRNAs from blood serum reflect these brain changes, offering potential for non-invasive diagnostic approaches. Our findings indicate TRAF6 mediated signaling regulate long-term CTE pathology and present targets for therapeutic development.