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The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ALS have nominated altered RNA metabolism as a disease mechanism. However, the RNAs regulated by TDP-43 in motor neurons and their connection to neuropathy remain to be identified. Here we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.Klim et al. illuminate pathomechanisms of ALS using pluripotent stem cells to identify transcripts altered in human motor neurons by perturbations to ALS protein TDP-43, finding the microtubule regulator STMN2 highly sensitive to TDP-43 malfunctions.

Background Fecal microbiota transplantation (FMT) has emerged as a key tool to explore the role of the microbiome-gut-brain axis in psychiatric disorders. However, the field is hindered by significant methodological inconsistencies. Methods A comprehensive literature search identified 31 studies performing FMT from human patients with psychiatric conditions into rodent models. Results None of the 31 studies followed an identical FMT protocol. Significant heterogeneity was observed across studies in rodent model selection, including germ-free, antibiotic-pretreated, or specific pathogen-free approaches, in antibiotic regimens, timing and microbiota depletion verification, as well as in FMT donor strategy, dosage, frequency, engraftment assessment, and behavioral testing schedules. Conclusions This review highlights the necessity for standardized methodologies in microbiome research. Evidence-based recommendations are provided to promote reproducibility in future work. Investigators are encouraged to publish transparent and rigorous protocols, to enhance the translational potential of microbiome-gut-brain axis research.

Discriminating between pathogens and commensals is a major dilemma faced by the immune system. Nunez et al . demonstrate that the recognition of bacterial pathogen type III secretion systems by the NLRC4 inflammasome is key to this discrimination. Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we found that intestinal phagocytes were anergic to ligands for Toll-like receptors (TLRs) or commensals but constitutively expressed the precursor to interleukin 1β (pro-IL-1β). After infection with pathogenic Salmonella or Pseudomonas , intestinal phagocytes produced mature IL-1β through the NLRC4 inflammasome but did not produce tumor necrosis factor (TNF) or IL-6. BALB/c mice deficient in NLRC4 or the IL-1 receptor were highly susceptible to orogastric but not intraperitoneal infection with Salmonella . That enhanced lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance. Thus, NLRC4-dependent production of IL-1β by intestinal phagocytes represents a specific response that discriminates pathogenic bacteria from commensal bacteria and contributes to host defense in the intestine.

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia 1 , 2 . The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration 3 – 9 . The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins 5 before its non-canonical translation into neural-toxic dipeptide proteins 3 , 4 . The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation 6 – 9 . Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria 10 , 11 protects C9orf72 -mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics—as well as transplanting gut microflora from a protective environment—attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system. Reduced abundance of immune-stimulating gut bacteria ameliorated the inflammatory and autoimmune phenotypes of mice with mutations in C9orf72 , which in the human orthologue are linked to amyotrophic lateral sclerosis and frontotemporal dementia.

Background Immune‐related changes impact clinical outcomes in people with Alzheimer's disease (AD). However, these changes have yet to translate into robust blood biomarkers of AD, in part due to high inter‐individual variation, small effect sizes, and the indirect relationship between peripheral blood and central nervous system changes. Method In this prospective cohort study of 55 subjects, 19 healthy controls (11 female and 8 male), 19 mild cognitive impairment (MCI) stage of AD (13 female and 6 male), 8 AD dementia (4 female and 4 male) and 9 frontotemporal lobar degeneration (FTD) (7 female and 2 male) individuals, we used mass cytometry to identify a sex‐specific immune cell signature in AD peripheral blood and cerebrospinal fluid (CSF). Dynamic contrast enhanced magnetic resonance (DCE‐MRI) imaging was used to assess regional blood‐brain barrier (BBB) permeability in subjects. Five patients contributed blood and CSF samples after one‐year longitudinal follow‐up. Result Peripheral blood immune cell responsiveness is more robust than the CSF immune cell signature and peaks earlier in the peripheral blood in the MCI stage among females and later in males at the AD dementia stage. To demonstrate clinical utility of this immune cell signature to identify the MCI stage of AD, we show its effect size exceeded that of Amyloid β42/40, phospho‐tau181, plasma phospho‐tau217, and cytokine signatures both in the plasma and CSF and was significantly elevated relative to FTD. The immune cell activation signature also correlated with MRI measures of hippocampal BBB permeability and cognitive outcomes. Conclusion The immune cell changes identified here were distinct among cellular phenotypes in peripheral blood and CSF in their responsiveness to AD pathological changes and show promise for novel biomarkers and future immune related therapeutics in AD.

Immune-related changes impact clinical outcomes in people with Alzheimer's disease (AD). However, these changes have yet to translate into robust blood biomarkers of AD, in part due to high inter-individual variation, small effect sizes, and the indirect relationship between peripheral blood and central nervous system changes. In this prospective cohort study of 55 subjects, 19 healthy controls (11 female and 8 male), 19 mild cognitive impairment (MCI) stage of AD (13 female and 6 male), 8 AD dementia (4 female and 4 male) and 9 frontotemporal lobar degeneration (FTD) (7 female and 2 male) individuals, we used mass cytometry to identify a sex-specific immune cell signature in AD peripheral blood and cerebrospinal fluid (CSF). Dynamic contrast enhanced magnetic resonance (DCE-MRI) imaging was used to assess regional blood-brain barrier (BBB) permeability in subjects. Five patients contributed blood and CSF samples after one-year longitudinal follow-up. Peripheral blood immune cell responsiveness is more robust than the CSF immune cell signature and peaks earlier in the peripheral blood in the MCI stage among females and later in males at the AD dementia stage. To demonstrate clinical utility of this immune cell signature to identify the MCI stage of AD, we show its effect size exceeded that of Amyloid β42/40, phospho-tau181, plasma phospho-tau217, and cytokine signatures both in the plasma and CSF and was significantly elevated relative to FTD. The immune cell activation signature also correlated with MRI measures of hippocampal BBB permeability and cognitive outcomes. The immune cell changes identified here were distinct among cellular phenotypes in peripheral blood and CSF in their responsiveness to AD pathological changes and show promise for novel biomarkers and future immune related therapeutics in AD.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1 + ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn’s disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2 , in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P -value <10 −3 , respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2 , but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.

Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we report that intestinal phagocytes are anergic to Toll-like receptor ligands or commensals, but constitutively express pro-interleukin-1β (proIL-1β). Upon infection with pathogenic Salmonella or Pseudomonas, intestinal phagocytes produce mature IL-1β through the NLRC4 inflammasome, but not tumor necrosis factor or IL-6. Mice deficient in NLRC4 or IL-1 receptor on a Balb/c background were highly susceptible to orogastric but not intraperitoneal infection with Salmonella. Increased lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment, and poor intestinal pathogen clearance. Thus, NLRC4-dependent IL-1β production by intestinal phagocytes represents a specific response discriminating pathogenic from commensal bacteria and contributes to host defense in the intestine.

Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we found that intestinal phagocytes were anergic to ligands for Toll-like receptors (TLRs) or commensals but constitutively expressed the precursor to interleukin 1[beta] (pro-IL-1[beta]). After infection with pathogenic Salmonella or Pseudomonas, intestinal phagocytes produced mature IL-1[beta] through the NLRC4 inflammasome but did not produce tumor necrosis factor (TNF) or IL-6. BALB/c mice deficient in NLRC4 or the IL-1 receptor were highly susceptible to orogastric but not intraperitoneal infection with Salmonella. That enhanced lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance. Thus, NLRC4-dependent production of IL-1[beta] by intestinal phagocytes represents a specific response that discriminates pathogenic bacteria from commensal bacteria and contributes to host defense in the intestine.