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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-43^Q331K, 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-43^Q331K. However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43^Q331K mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43^Q331K-mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD.

SUBMITTER: White MA

PROVIDER: S-EPMC6819591 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

White Matthew A MA Lin Ziqiang Z Kim Eugene E Henstridge Christopher M CM Pena Altamira Emiliano E Hunt Camille K CK Burchill Ella E Callaghan Isobel I Loreto Andrea A Brown-Wright Heledd H Mead Richard R Simmons Camilla C Cash Diana D Coleman Michael P MP Sreedharan Jemeen J

Acta neuropathologica communications 20191028 1

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 ...[more]

PMID: 31661035

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Project description:BackgroundUpper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies.MethodsNovel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP-43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU-9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses.ResultsProblems with mitochondria and ER are conserved in diseased UMNs among different species. NU-9 has drug-like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU-9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP-43 pathology, two distinct and important overarching causes of motor neuron degeneration.ConclusionsMechanism-focused and cell-based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU-9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.

Dataset Information

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

Publications

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

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