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.

Mice bearing the mutated gene for Cu/Zn superoxide dismutase (G93A) are a good model for human amyotrophic lateral sclerosis (ALS). They develop progressive limb paralysis paralleled by loss of motor neurons of the cervical and lumbar spinal cord, which starts at 3-3.5 months of age and ends with death at 4-5 months. Several treatments have been attempted to delay clinical symptoms and to extend lifespan, and some have had modest beneficial effects. One such treatment, based on long-term administration of valproic acid (VPA), resulted in controversial results. We report here that, while dietary supplementation with high VPA dosage slows down motor neuron death, as assessed by measurement of a specific marker for cholinergic neurons in the spinal cord, it has no significant effect on lifespan. Recently, the hypothesis has been put forward that a deficiency of retinoic acid (RA) and its signaling may have a role in ALS. We report that long-term dietary supplementation with RA has no effect on the decrease of the cholinergic marker in the spinal cord, but it significantly shortens lifespan of G93A mice.

Gene expression is controlled by several epigenetic mechanisms involving post-translational modification of histones (acetylation, phosphorylation and others). These mechanisms in the brain are not only important for normal function but also for the development of pathologies when their derangement does occur. The present review deals with post-translational modifications of histones in two neurodegenerative diseases characterized by different etiology and pathological progression, Huntington's disease and Parkinson's disease. A relatively large body of evidence supports an important role of these mechanisms in Huntington's disease while knowledge of similar mechanisms in Parkinson's disease is at a lower degree of understanding. Starting from available information on pathologies, the present state of possible therapeutic targets is considered and future developments are discussed.

Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerised tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.

Recent evidence suggests that nitric oxide (NO) has a remarkable anti-proliferative action towards dividing neural precursor cells as well as towards cells giving rise to neural-derived tumors. The present paper summarizes essential literature-derived information on this issue and provides novel experimental evidence for these NO-mediated actions regarding a well characterized population of neuronal precursors, the cerebellar granule cell precursors and a cell line of medulloblastoma, a pediatric tumor originating from these same precursor cells undergoing deregulated proliferation. Evidence is presented regarding the NO-mediated regulation of proliferation of neuronal precursor cells both during developmental and adult neurogenesis. Then, the role of NO in the control of proliferation of neural-derived tumor cells, such as PC12 and neuroblastoma cells, is discussed. Novel experimental data are provided documenting the anti-proliferative action of NO towards basal and mitogen-stimulated division of rat cerebellar granule cell precursors, as well as towards medulloblastoma DAOY cells. Finally, some molecular correlates of NO action on cell cycle regulation are discussed. Overall, the data presented and discussed here highlight similarities at the molecular level between physiologic processes regulating normal proliferation of neural precursors and pathologic deregulation of these processes leading to tumor formation.