Oligodendrocytes in amyotrophic lateral sclerosis and frontotemporal dementia: the new players on stage.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal adult-onset neurodegenerative disorders that share clinical, neuropathological and genetic features, which forms part of a multi-system disease spectrum. The pathological process leading to ALS and FTD is the result of the combination of multiple mechanisms that operate within specific populations of neurons and glial cells. The implication of oligodendrocytes has been the subject of a number of studies conducted on patients and related animal models. In this review we summarize our current knowledge on the alterations specific to myelin and the oligodendrocyte lineage occurring in ALS and FTD. We also consider different ways by which specific oligodendroglial alterations influence neurodegeneration and highlight the important role of oligodendrocytes in these two intrinsically associated neurodegenerative diseases.

Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86R and FusΔNLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93A and FusΔNLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data. METHODS: We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system. RESULTS: Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects. CONCLUSIONS: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.

Cystatin C based estimation of chronic kidney disease and amyotrophic lateral sclerosis in the ALS registry Swabia: associated risk and prognostic value.

Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case-control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m2). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case-control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.

Nutritional and metabolic factors in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that is classically thought to impact the motor system. Over the past 20 years, research has started to consider the contribution of non-motor symptoms and features of the disease, and how they might affect ALS prognosis. Of the non-motor features of the disease, nutritional status (for example, malnutrition) and metabolic balance (for example, weight loss and hypermetabolism) have been consistently shown to contribute to more rapid disease progression and/or earlier death. Several complex cellular changes observed in ALS, including mitochondrial dysfunction, are also starting to be shown to contribute to bioenergetic failure. The resulting energy depletion in high energy demanding neurons makes them sensitive to apoptosis. Given that nutritional and metabolic stressors at the whole-body and cellular level can impact the capacity to maintain optimal function, these factors present avenues through which we can identify novel targets for treatment in ALS. Several clinical trials are now underway evaluating the effectiveness of modifying energy balance in ALS, making this article timely in reviewing the evidence base for metabolic and nutritional interventions.

Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes.

Cytoplasmic mislocalization of the nuclear Fused in Sarcoma (FUS) protein is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS accumulation is recapitulated in the frontal cortex and spinal cord of heterozygous Fus∆NLS/+ mice. Yet, the mechanisms linking FUS mislocalization to hippocampal function and memory formation are still not characterized. Herein, we show that in these mice, the hippocampus paradoxically displays nuclear FUS accumulation. Multi-omic analyses showed that FUS binds to a set of genes characterized by the presence of an ETS/ELK-binding motifs, and involved in RNA metabolism, transcription, ribosome/mitochondria and chromatin organization. Importantly, hippocampal nuclei showed a decompaction of the neuronal chromatin at highly expressed genes and an inappropriate transcriptomic response was observed after spatial training of Fus∆NLS/+ mice. Furthermore, these mice lacked precision in a hippocampal-dependent spatial memory task and displayed decreased dendritic spine density. These studies shows that mutated FUS affects epigenetic regulation of the chromatin landscape in hippocampal neurons, which could participate in FTD/ALS pathogenic events. These data call for further investigation in the neurological phenotype of FUS-related diseases and open therapeutic strategies towards epigenetic drugs.

Skeletal muscle in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.

Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.

Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers.

BACKGROUND: The emergence of potentially effective new therapies for genetic forms of amyotrophic lateral sclerosis (ALS) necessitates the identification of biomarkers to facilitate early treatment, prior to the onset of motor symptoms. Here, we sought to investigate whether metabolic alterations are detectable in presymptomatic ALS gene mutation carriers, and whether such alterations precede neurofilament light chain (NfL) changes in serum. METHODS: Between 02/2014 and 11/2021, we prospectively studied 60 presymptomatic ALS gene mutation carriers (40% male, age 48.7 ± 14.9; 28 C9orf72, 22 SOD1, 10 other) compared to 73 individuals from the same families (47% male, age 47.4 ± 12.9) without pathogenic mutations as controls. Bioimpedance analysis (BIA) and indirect calorimetry were performed, and Body Mass Index (BMI), Fat Mass (FM), Body Fat Percentage, Body Water (BW), Lean Body Mass (LBM), Extracellular Mass (ECM), Body Cell Mass (BCM), ECM/BCM ratio, Cells Percentage, Phase Angle, Resting Metabolic Rate (RMR), Metabolic Ratio (MR), and NfL were measured. Participants and evaluators were blinded regarding gene carrier status. FINDINGS: Presymptomatic ALS gene carriers showed reduced LBM (p = 0.02), BCM (p = 0.004), Cells Percentage (p = 0.04), BW (p = 0.02), Phase Angle (p = 0.04), and increased ECM/BCM ratio (p = 0.04), consistently indicating a loss of metabolically active body cells. While in C9orf72 mutation carriers all tissue masses were reduced, only metabolically active tissue was affected in SOD1 mutation carriers. Unexpectedly, RMR (p = 0.009) and MR (p = 0.01) were lower in presymptomatic ALS gene carriers compared to non-carriers. NfL serum levels were similar in mutation carriers and non-carriers (p = 0.60). INTERPRETATION: The observed metabolic phenomena might reflect reduced physical activity and/or preemptive, insufficient compensatory mechanisms to prepare for the later hypermetabolic state. As pre-symptomatic biomarkers we propose ECM/BCM ratio and Phase Angle for SOD1, and a 4-compartment affection in BIA for C9orf72 mutation carriers. FUNDING: This work was an investigator-initiated trial. On the German side, there was no institutional or industrial funding. On the Swedish side, this work was supported by grants from the Swedish Brain Foundation (grants nr. 2013-0279, 2016-0303, 2018-0310, 2020-0353), the Swedish Research Council (grants nr. 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305, 2020.0232), the Ulla-Carin Lindquist Foundation, Umeå University (223-2808-12, 223-1881-13, 2.1.12-1605-14) and the Västerbotten County Council (grants nr 56103-7002829), King Gustaf V:s and Queen Victoria's Freemason's Foundation.

Integrative genetic analysis illuminates ALS heritability and identifies risk genes.

Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10-03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.

A conditional null allele of Dync1h1 enables targeted analyses of dynein roles in neuronal length sensing.

Size homeostasis is a fundamental process in biology and is particularly important for large cells such as neurons. We previously proposed a motor-dependent length-sensing mechanism wherein reductions in microtubule motor levels would be expected to accelerate neuronal growth, and validated this prediction in dynein heavy chain 1 Loa mutant (Dync1h1Loa) sensory neurons. Here, we describe a new mouse model with a conditional deletion allele of exons 24 and 25 in Dync1h1. Homozygous Islet1-Cre-mediated deletion of Dync1h1 (Isl1-Dync1h1-/-), which deletes protein from the motor and sensory neurons, is embryonic lethal, but heterozygous animals (Isl1-Dync1h1+/-) survive to adulthood with ∼50% dynein expression in targeted cells. Isl1-Dync1h1+/- sensory neurons reveal accelerated growth, as previously reported in Dync1h1Loa neurons. Moreover, Isl1-Dync1h1+/- mice show mild impairments in gait, proprioception and tactile sensation, similar to what is seen in Dync1h1Loa mice, confirming that specific aspects of the Loa phenotype are due to reduced dynein levels. Isl1-Dync1h1+/- mice also show delayed recovery from peripheral nerve injury, likely due to reduced injury signal delivery from axonal lesion sites. Thus, conditional deletion of Dync1h1 exons 24 and 25 enables targeted studies of the role of dynein in neuronal growth.

Morphological alterations of the hypothalamus in idiopathic intracranial hypertension.

Background: The pathophysiology of idiopathic intracranial hypertension (IIH), a condition characterized by raised intracranial pressure, is not well understood. Objectives: We hypothesized that the hypothalamus might exhibit alterations in patients with IIH, based on its established association with obesity and the potential role of hormonal and metabolic factors in IIH. Design: Retrospective single-center cohort study. Methods: Thirty-three individuals with IIH and 40 matched healthy individuals were studied, including levels of the hormones and proteins leptin, adiponectin, ghrelin, insulin, growth/differentiation factor 15 (GDF15), somatostatin, and melatonin. In vivo high-resolution T1-weighted magnetic resonance imaging (MRI) data were analyzed by quantification of hypothalamic volumes using a well-established segmentation method, separate for the anterior and the posterior hypothalamic subvolumes. An additional analysis was performed using age, gender, and BMI-matched subgroups of 20 IIH patients and 20 controls. Results: The analysis of laboratory values showed significantly increased insulin, leptin, and melatonin levels for IIH patients in comparison to controls, while adiponectin levels were decreased in IIH; however, only melatonin level differences could be confirmed in the analysis with BMI matching. There was no statistical difference in total hypothalamus volumes between IIH and controls, but the hypothalamic morphology was altered in IIH patients with a lower volume of the anterior part of the hypothalamus and a higher volume of the posterior part; these results were identical in the analysis of the BMI-matched groups. The correlation analyses between hormonal changes and hypothalamic morphology did not achieve significant results. Conclusion: In this exploratory study, morphological abnormalities of the hypothalamus were observed to be associated with the IIH complex, although the mechanism remains to be unraveled. These findings expand the metabolic phenotype of IIH, but further functional studies are necessary to corroborate these data.

Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis.

Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT2B receptor (5-HT2BR) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1G86R mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HT2BR agonist : BW723C86 (BW), in the Sod1G86R mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression.

Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation.

Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a wild-type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (Fus∆NLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-type FUS completely rescued the early lethality caused by the two Fus∆NLS alleles, and improved the age-dependent motor deficits and reduced lifespan caused by heterozygous expression of mutant FUS∆NLS. Mechanistically, wild-type FUS decreased the load of cytoplasmic FUS, increased retention of introns 6 and 7 in the endogenous mouse Fus mRNA, and decreased expression of the mutant mRNA. Thus, the wild-type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent wild-type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.

Dysregulation of energy homeostasis in amyotrophic lateral sclerosis.

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting upper and lower motor neurons, inexorably leading to an early death. Defects in energy metabolism have been associated with ALS, including weight loss, increased energy expenditure, decreased body fat mass and increased use of lipid nutrients at the expense of carbohydrates. We review here recent findings on impaired energy metabolism in ALS, and its clinical importance. RECENT FINDINGS: Hypothalamic atrophy, as well as alterations in hypothalamic peptides controlling energy metabolism, have been associated with metabolic derangements. Recent studies showed that mutations causing familial ALS impact various metabolic pathways, in particular mitochondrial function, and lipid and carbohydrate metabolism, which could underlie these metabolic defects in patients. Importantly, slowing weight loss, through high caloric diets, is a promising therapeutic strategy, and early clinical trials indicated that it might improve survival in at least a subset of patients. More research is needed to improve these therapeutic strategies, define pharmacological options, and refine the population of ALS patients that would benefit from these approaches. SUMMARY: Dysfunctional energy homeostasis is a major feature of ALS clinical picture and emerges as a potential therapeutic target.

Hypothalamus and weight loss in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder. While initially pathophysiology was thought to be restricted to motor deficits, it is increasingly recognized that patients develop prominent changes in weight and eating behavior that result from and mediate the underlying neurodegenerative process. These changes include alterations in metabolism, lipid levels, and insulin resistance. Emerging research suggests that these alterations may be mediated through changes in the hypothalamic function, with atrophy of the hypothalamus shown in both ALS patients and also presymptomatic genetic at-risk patients. This chapter reviews the evidence for hypothalamic involvement in ALS, including melanocortin pathways and potential treatment targets.

Disruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients.

BACKGROUND: Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. METHODS: The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. RESULTS: Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. CONCLUSION: This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.

Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects.

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization.