Role of Sarm1 in TBI-accentuated C9orf72 Frontotemporal Dementia

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases without available therapy. Epidemiological data suggest that traumatic brain injury (TBI) is a risk factor for ALS and FTD; TBI, ALS, and FTD share several pathological findings, including neuronal and axonal degeneration, neuroinflammation, and mislocalization of TDP-43. Axonal pathology, an early event after TBI, promotes TDP-43 dysregulation and may serve as a trigger for neurodegenerative processes. Axon loss can be driven by a genetically encoded program governed by the axon destruction factor SARM1, rendering it an attractive target for treating many neurological diseases. We and others have reported that SARM1 clearly promotes TBI-associated neurodegeneration and a role for SARM1 has also been proposed in ALS/FTD. Since most cases of ALS/FTD are sporadic, involving multiple risk factors, we will test the hypothesis that the adverse role of SARM1 in ALS/FTD is revealed in mice using a “two-hit model” (TBI combined with a C9orf72 ALS/FTD gene defect) that reflect the combined risks of a harmful environmental stimulus with genetic risk in sporadic ALS/FTD patients. The most common cause of dominantly inherited ALS and FTD is a hexanucleotide repeat expansion (HRE) in the C9orf72 gene (c9ALS/FTD). However, it remains to be established whether (1) TBI can trigger events that accelerate pathology and clinical disease in HRE carriers, and (2) whether there are interventions to blunt the impact of TBI and attenuate adverse neuropathological events. Our pilot data provide proof-of-concept that repetitive mild TBI (rTBI) causes extensive neuronal and axonal loss and persistent neuroinflammation at 12 months after injury in a transgenic C9orf72 (C9BACtg/tg) mouse model. In Aim1 we will conduct a time-course experiment in non-transgenic and transgenic C9BACtg/tg mice to quantify pathology in frontal and temporal cortices for up to 12 months after rTBI or sham surgery. We will use immunohistochemistry markers for neurons, axons, microglia, astroglia, and TDP-43; WB and qPCR for TDP-43 expression; cytometric bead array for interleukin-1β expression; fluorescence in situ hybridization for RNA foci; and Meso Scale Discovery assay for dipeptide repeats as markers of c9ALS/FTD pathology after rTBI or sham surgery. A battery of motor and cognitive tests will be used to assess behavioral deficits. These experiments will test the hypothesis that following rTBI c9ALS/FTD mice will manifest exaggerated behavioral, microscopic, and molecular pathology, and accelerated disease-onset. In Aim2 we will use our established colony of C9BACtg/tgxSarm1-/- mice, to conduct a time- course experiment analogous to Aim1 to ascertain if genetic ablation of Sarm1 attenuates neurodegeneration and behavioral deficits following rTBI. These experiments will test the hypothesis that following rTBI, behavioral, microscopic, and molecular pathology will be attenuated in c9ALS/FTD mice by inactivation of Sarm1. Together, these experiments will illuminate mechanisms underlying c9ALS/FTD after rTBI by identifying cellular and molecular response pathways and providing insights into principles governing the interplay between TDP-43 and neurodegeneration in c9ALS/FTD. Our studies may also define SARM1 as a therapeutic target to mitigate the devasting consequences of this and other TBI- associated neurodegenerative diseases such as Alzheimer's disease (AD) and related dementias (ADRD).