Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.

Does genetic anticipation occur in familial Alexander disease?

Alexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent-offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon.

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

Relative preservation of triceps over biceps strength in upper limb-onset ALS: the 'split elbow'.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system. The split hand sign in ALS refers to observed preferential weakness of the lateral hand muscles, which is unexplained. One possibility is larger cortical representation of the lateral hand compared with the medial. Biceps strength is usually preserved relative to triceps in neurological conditions, but biceps has a larger cortical representation and might be expected to show preferential weakness in ALS. METHODS: Using the South-East England Register for Amyotrophic Lateral Sclerosis, we performed a retrospective longitudinal cohort study and extracted the modified Medical Research Council (MRC) muscle strength score for biceps and triceps in patients with a diagnosis of upper limb-onset ALS in the 19-year period 1996-2015. A Wilcoxon signed-rank test was used to assess the relative strength of the muscles within the total sum of the upper limbs involved in the study. RESULTS: There were 659 people with upper limb onset of weakness. In 215 there were insufficient data to perform the analysis, and a further 33 were excluded for other reasons, leaving 411 for analysis. Biceps was stronger than triceps in 87 limbs, and triceps was stronger than biceps in 258 limbs, with no difference seen in the remaining 477. Triceps strength scores (mean rank=186.1) were higher than ipsilateral biceps strength scores (mean rank=134.2), Z=-10.1, p<0.001 (two-tailed). CONCLUSION: Triceps strength is relatively preserved compared with biceps in ALS. This is consistent with a broadly corticofugal hypothesis of selective vulnerability, in which susceptibility might be associated with larger cortical representation.

Amyotrophic lateral sclerosis: recent genetic highlights.

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS), like other neurodegenerative diseases, remains incurable, but gene mutations linked to ALS are providing clues as to how to target therapies. It is important for researchers to keep abreast of the rapid influx of new data in ALS, and we aim to summarize the major genetic advances made in the field over the past 2 years. RECENT FINDINGS: Significant variation in seven genes has recently been found in ALS: TBK1, CCNF, GLE1, MATR3, TUBA4A, CHCHD10 and NEK1. These have mostly been identified through large exome screening studies, though traditional linkage approaches and candidate gene screening remain important. We briefly update C9orf72 research, noting in particular the development of reagents to better understand the normal role of C9orf72 protein. SUMMARY: Striking advances in our understanding of the genetic heterogeneity of ALS continue to be made, year on year. These implicate proteostasis, RNA export, nuclear transport, the cytoskeleton, mitochondrial function, the cell cycle and DNA repair. Functional studies to integrate these hits are needed. By building a web of knowledge with interlinked genes and mechanisms, it is hoped we can better understand ALS and work toward effective therapies.

Amyotrophic lateral sclerosis: Problems and prospects.

Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disorder of motoneurons, which may occur concurrently with frontotemporal dementia. Genetic analyses of the ∼10% of ALS cases that are dominantly inherited provide insight into ALS pathobiology. Two broad themes are evident. One, prompted by investigations of the SOD1 gene, is that conformational instability of proteins triggers downstream neurotoxic processes. The second, from studies of the TDP43, FUS, and C9orf72 genes, is that perturbations of RNA processing can be highly adverse in motoneurons. Several investigations support the concept that non-neuronal cells (microglia, astroglia, oligodendroglia) participate in the degenerative process in ALS. Recent data also emphasize the importance of molecular events in the axon and distal motoneuron terminals. Only 1 compound, riluzole, is approved by the US Food and Drug Administration for ALS; several therapies are in clinical trials, including 2 mesenchymal stem cell trials. The challenges and unmet needs in ALS emphasize the importance of new research directions: high-throughput sequencing of large DNA sets of familial and sporadic ALS, which will define scores of candidate ALS genes and pathways and facilitate studies of epistasis and epigenetics; infrastructures for candidate gene validation, including in vitro and in vivo modeling; valid biomarkers that elucidate causative molecular events and accelerate clinical trials; and in the long term, methods to identify environmental toxins. The unprecedented intensity of research in ALS and the advent of extraordinary technologies (rapid, inexpensive DNA sequencing; stem cell production from skin-derived fibroblasts; silencing of miscreant mutant genes) bode well for discovery of innovative ALS therapies.

Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue.

Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.

Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the FUS gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies.

Falsely pessimistic prognosis by EEG in post-anoxic coma after cardiac arrest: the borderland of nonconvulsive status epilepticus.

BACKGROUND: Prognostication following anoxic coma relies on clinical assessment and is assisted by neurophysiology. A non-evolving EEG spike burst/isoelectric suppression pattern after the first 24 hours almost invariably indicates poor outcome, while an evolving pattern implies nonconvulsive status epilepticus (NCSE) that may "hide" surviving brain activity and is amenable to treatment. CASE STUDY: We present the case of a 53-year-old woman who had a witnessed out-of-hospital ventricular fibrillation cardiac arrest, was resuscitated by paramedics, but remained comatose. An EEG, performed 36 hours post-insult, showed an unremitting, non-evolving, unresponsive 2-6 Hz high-voltage spike burst/isoelectric suppression pattern, which remained unchanged at 96 hours post-insult, following therapeutic hypothermia. During this period, she was completely off sedation and taking triple antiepileptic treatment, without systemic confounding disorders. Although the initial pattern was indicative of poor neurological outcome, she eventually made meaningful functional recovery; the last EEG showed satisfactory background rhythms and stimulus-induced epileptiform discharges without seizures. CONCLUSION: In post-anoxic coma, non-evolving >2 Hz spike burst/isoelectric suppression pattern may still reflect NCSE and therefore should be considered in the diagnostic EEG criteria for NCSE. Such borderline patterns should not dissuade physicians from intensifying treatment until more confident prognostication can be made.

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia.

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 pre-symptomatic 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 was 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. Computerized 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.

Blowing Hot and Cold in ALS: The Duality of TBK1.

Mutations in TANK-binding kinase 1 (TBK1) are linked to ALS-FTD. In this issue of Neuron, Gerbino et al. (2020) show how missense mutations in the kinase domain of TBK1 differentially affect disease onset and progression in an ALS mouse model.

Loss of highwire Protects Against the Deleterious Effects of Traumatic Brain Injury in Drosophila Melanogaster.

Traumatic brain injury is a major global cause of death and disability. Axonal injury is a major underlying mechanism of TBI and could represent a major therapeutic target. We provide evidence that targeting the axonal death pathway known as Wallerian degeneration improves outcome in a Drosophila Melanogaster model of high impact trauma. This cell-autonomous neurodegenerative pathway is initiated following axon injury, and in Drosophila, involves activity of the E3 ubiquitin ligase highwire. We demonstrate that a loss-of-function mutation in the highwire gene rescues deleterious effects of a traumatic injury, including-improved functional outcomes, lifespan, survival of dopaminergic neurons, and retention of synaptic proteins. This data suggests that highwire represents a potential therapeutic target in traumatic injury.

Female sex mitigates motor and behavioural phenotypes in TDP-43Q331K knock-in mice.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders. ALS is more commonly seen in men than women and the same may be the case for FTD. Preclinical models demonstrating sex-specific vulnerability may help to understand female resistance to ALS-FTD and thereby identify routes to therapy. We previously characterised a TDP-43Q331K knock-in mouse, which demonstrated behavioural phenotypes reminiscent of ALS-FTD in males. Here we present our behavioural observations of female TDP-43Q331K mutants. Female TDP-43Q331K knock-in mice displayed increased weight relative to wild-type and increased food intake at 20 months of age, much later than previously observed in male mutants. Spontaneous digging behaviour was initially normal and only declined in mutants in the second year of life. Gait analysis using Catwalk ( https://www.noldus.com/catwalk-xt ) found significant deficits in the second year of life, while nocturnal running behaviour was attenuated from ~ 250 days of life. These results indicate that while female TDP-43Q331K knock-in mice do display progressive behavioural phenotypes, these are less severe than we previously noted in male mutants. Further studies of male and female TDP-43Q331K knock-in mice may help to unravel the mechanisms underlying sex-specific vulnerability in ALS-FTD.

Coexistence of perseveration and apathy in the TDP-43Q331K knock-in mouse model of ALS-FTD.

Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS-FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS-FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS-FTD.

Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS.

Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.

Predicting the future of ALS: the impact of demographic change and potential new treatments on the prevalence of ALS in the United Kingdom, 2020-2116.

Objective: To model the effects of demographic change under various scenarios of possible future treatment developments in ALS. Methods: Patients diagnosed with ALS at the King's College Hospital Motor Nerve Clinic between 2004 and 2017, and living within the London boroughs of Lambeth, Southwark, and Lewisham (LSL), were included as incident cases. We also ascertained incident cases from the Canterbury region over the same period. Future incidence of ALS was estimated by applying the calculated age- and sex-specific incidence rates to the UK population projections from 2020 to 2116. The number of prevalent cases for each future year was estimated based on an established method. Assuming constant incidence, we modelled four possible future prevalence scenarios by altering the median disease duration for varying subsets of the population, to represent the impact of new treatments. Results: The total number of people newly diagnosed with ALS per year in the UK is projected to rise from a baseline of 1415 UK cases in 2010 to 1701 in 2020 and 2635 in 2116. Overall prevalence of ALS was predicted to increase from 8.58 per 100,000 persons in 2020 to 9.67 per 100,000 persons in 2116. Halting disease progression in patients with C9orf72 mutations would yield the greatest impact of the modelled treatment scenarios, increasing prevalence in the year 2066 from a baseline of 9.50 per 100,000 persons to 15.68 per 100,000 persons. Conclusions: Future developments in treatment would combine with the effects of demographic change to result in more people living longer with ALS.

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

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.

Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia.

Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506S UBQLN2 mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of published UBQLN2 mutations demonstrated that only proline-rich domain mutations contribute to a significantly earlier age of onset in male patients (p = 0.0026).

TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD.

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene. Furthermore, a new approach to stratify transcriptomic data by phenotype in differentially affected mutant mice revealed 471 changes linked with improved behavior. These changes included downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.