Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a ‘dying-back’ disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43Q331K, YFP-H double transgenic mouse. Sarm1 deletion attenuated motor axon degeneration and neuromuscular junction denervation. Motor neuron cell bodies were also significantly protected. Deletion of Sarm1 also attenuated loss of layer V pyramidal neuronal dendritic spines in the primary motor cortex. Structural MRI identified the entorhinal cortex as the most significantly atrophic region, and histological studies confirmed a greater loss of neurons in the entorhinal cortex than in the motor cortex, suggesting a prominent FTD-like pattern of neurodegeneration in this transgenic mouse model. Despite the reduction in neuronal degeneration, Sarm1 deletion did not attenuate age-related behavioural deficits caused by TDP-43Q331K. However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43Q331K mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43Q331K-mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD.Electronic supplementary materialThe online version of this article (10.1186/s40478-019-0800-9) contains supplementary material, which is available to authorized users.

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

“…For micro-CT, 24-month-old male mice were perfused with 2% paraformaldehyde, and heads were processed as previously described (White et al, 2019). Heads were scanned using a Scanco µCT50 micro-CT scanner (Scanco, Brüttisellen, Switzerland).…”

“…1D). Furthermore, voxelwise analysis using tensor-based morphometry (TBM) (White et al, 2019) revealed widespread statistically significant (FWE P<0.05) volume reductions in cortical, subcortical and cerebellar regions in TDP-43 Q331K/Q331K compared to wild-type mice ( Figure 1E).…”

SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury through NF-κB signaling

“…Previous researches have clarified the function and mechanism of SARM1 in neuroinflammation and axon degeneration after injuries 61 - 63 . SARM1 is widely expressed in various tissues and cell types, and has diversity functions.…”

Sarm1 knockout protects against early but not late axonal degeneration in experimental allergic encephalomyelitis

“…Sarm1 knockout mice showed reduced clinical severity and reduced axonal loss in animal models of traumatic brain injury [10,28]. Sarm1 deletion was beneficial in the TDP-43 Q331K model of amyotrophic lateral sclerosis-frontotemporal dementia [29], but had no significant impact on axonal loss or clinical course of mutant SOD1 model of amyotrophic lateral sclerosis [30]. Therefore, the contribution of SARM1 is likely to be disease-specific.…”