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Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Since the reduction of pathogenic mutant HTT messenger RNA is therapeutic, we developed a mutant allele-sensitive CAGEX RNA-targeting CRISPR–Cas13d system (Cas13d–CAGEX) that eliminates toxic CAGEX RNA in fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show that intrastriatal delivery of Cas13d–CAGEX via an adeno-associated viral vector selectively reduces mutant HTT mRNA and protein levels in the striatum of heterozygous zQ175 mice, a model of HD. This also led to improved motor coordination, attenuated striatal atrophy and reduction of mutant HTT protein aggregates. These phenotypic improvements lasted for at least eight months without adverse effects and with minimal off-target transcriptomic effects. Taken together, we demonstrate proof of principle of an RNA-targeting CRISPR–Cas13d system as a therapeutic approach for HD, a strategy with implications for the treatment of other dominantly inherited disorders.

Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical–molecular–biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition. The iPS spinal neurons were blood derived from each patient and these cells underwent multi-omic analytics including whole-genome sequencing, RNA transcriptomics, ATAC-sequencing and proteomics. The intent of these data is for the generation of integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlying mechanisms of disease, including subgroup identification. A web portal for open-source sharing of all data was developed for widespread community-based data analytics.

Huntington’s disease (HD) results from a CAG repeat expansion in the gene for Huntington (HTT) resulting in expansion of the polyglutamine (Q) tract in the mutant protein (mHTT). Synaptic changes are early manifestations of neuronal dysfunction in HD. However, the mechanism(s) by which mHTT impacts synapse formation and function is not well defined. Herein we explored HD pathogenesis in the BACHD and the ΔN17-BACHD mouse models of HD by examining cortical synapse formation and function in primary cultures maintained for up to 35 days (DIV35). We identified synapses by immunostaining with antibodies against pre-synaptic (Synapsin 1) and a post-synaptic (PSD95) marker. Consistent with earlier studies, cortical neurons from both WT and the HD models began to form synapses at DIV14; at this age there were no genotypic differences in synapse numbers. However, from DIV21 through DIV35 BACHD neurons showed progressively smaller numbers of synapses relative to WT neurons. Remarkably, BACHD synaptic deficits were completely rescued by treating cultures with BDNF. Building on earlier studies using reagents inspired by the chaperonin TRiC, we found that addition of the recombinant apical domain of CCT1 partially rescued synapse number. Unexpectedly, unlike BACHD cultures, synapses in ΔN17-BACHD cultures showed a progressive increase in number as compared to WT neurons, thus distinguishing synaptic changes in these HD models. Using multielectrode arrays, we discovered age-related functional deficits in BACHD cortical cultures with significant differences present by DIV28. As for synapse number, BDNF treatment prevented most synaptic deficits, including mean firing rate, spikes per burst, inter-burst interval, and synchrony. The apical domain of CCT1 showed similar, albeit less potent effects. These data are evidence that deficits in HD synapse number and function can be replicatedin vitroand that treatment with either BDNF or a TRiC-inspired reagent can prevent them. Our findings support the use of cellular models to further explicate HD pathogenesis and its treatments.

Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood–brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington’s disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM–ITG interface in astrocytes and brain microvascular endothelial cells and found ECM–ITG dysregulation in human iPSC-derived cells that may contribute to the dysfunction of the BBB in HD. This disruption has functional consequences since reducing ITG expression in glia in an HD Drosophila model suppressed disease-associated CNS dysfunction. Since ITGs can be targeted therapeutically and manipulating ITG signaling prevents neurodegeneration in other diseases, defining the role of ITGs in HD may provide a novel strategy of intervention to slow CNS pathophysiology to treat HD.

SummaryHuntington’s disease (HD) is a neurodegenerative disease caused by an expanded CAG repeat within the Huntingtin (HTT) gene having dysregulated cellular homeostasis in the central nervous system, particularly in the striatum and cortex. Astrocytes establish and maintain neuronal functions through the secretion of soluble factors and physical interactions with other neurovascular unit cell types. Under pathological conditions, astrocytes can become reactive, causing cell state transitions that affect brain function. To investigate transitions between cellular states in unaffected and HD astrocytes at high resolution, single-nuclei RNA-sequencing (snRNA-seq) was performed on human HD patient induced pluripotent stem cell (iPSC)-derived astrocytes and on striatal and cortical tissue from a rapidly progressing HD mouse model (R6/2). Analysis of HD human and mouse astrocytes revealed both models have alterations in morphology, glutamate uptake, and dysregulation of astrocyte identity and maturation, whereas dysregulated actin-mediated signaling was unique to human iPSC-derived astrocytes. Representative proteins showed altered levels by Western. In both species, HD transcriptional changes reveal potential astrocyte maturation deficits that were potentially driven by astrogliogenesis transcription factors, including ATF3 and NFIA. When perturbed in a drosophila model of HD, knockdown of NFIA in glia rescued the climbing deficit. These data further support the hypothesis that mutant HTT induces dysregulated astrocyte cell states resulting in dysfunctional astrocytic properties, suggests that some of these states are cell autonomous and maybe unique to human HD, and implicate ATF3 and maturation deficits in HD pathogenesis.

The complexity of affected brain regions and cell types is a challenge for Huntington’s disease (HD) treatment. Here we used single nucleus RNA sequencing (snRNAseq) to investigate mechanism of pathology in the cortex and striatum from R6/2 mice at 8 and 12w and in three regions of human HD post-mortem tissue. We identified cell type-specific and cell agnostic signatures and found changes suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) were arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 were negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells showed decreased accessibility of sites regulated by OL maturation genes. Glucose and lipid metabolism were implicated in abnormal cell maturation and PRKCE and Thiamine Pyrophosphokinase 1 were identified as central genes. High dose thiamine/biotin treatment of R6/1 HD mice to target thiamine metabolism not only restored OL maturation, but also rescued pathology in neurons. These findings reveal insights into HD OL pathology that spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.

Introduction: To report a case of a Hispanic girl with late-onset Retinoblastoma (Rb) who was misdiagnosed as a pars planitis prior to referral. Nearly 95% of all Rb cases are detected before age 5, and this patient was 8 years-old. Methods: Case report of a late-onset Retinoblastoma with anterior chamber (AC) involvement plus the presence of an Ahmed valve. The patient had a history of a couple of months of topical therapy comprising medication for glaucoma, systemic steroids, and a filtration surgery (Ahmed valve), after that a biopsy was performed prior to referral. Upon arrival at our clinic, we performed an examination under anesthesia (EUA) and a B-scan ultrasound (US). Results: Unilateral Retinoblastoma with an Ahmed valve in an AC filled with Rb seeds was diagnosed with the EUA and US in the left eye. An orbital exenteration with map biopsies of the left orbital cavity was performed with confirmation by histopathology of a poorly differentiated endophytic retinoblastoma with Bruch’s membrane invasion. Follow-up sessions were then arranged as well as subsequent systemic chemotherapy cycles. Conclusion: Given the rare incidence of retinoblastoma in children older than 5 years old, it can be easily mistaken for other differential diagnoses and treated with filtration surgeries that could put the patient’s life at risk. In this report, late-onset Rb diagnosis is highlighted as a differential diagnosis in children and adults with atypical uveitis, which required a multidisciplinary approach.

Huntington’s Disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. Patient-derived induced pluripotent stem cells (iPSCs) can help understand disease; however, defining pathological biomarkers is challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered mitochondria with enlarged granules and distorted cristae, and thin sheet aggregates in double membrane-bound organelles. We used artificial intelligence to quantify mitochondrial granules, and proteomics showed differential protein content in HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC-neurons and reduced phenotypes in BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

Background: In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington’s disease (HD) progression. Objective: The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes. Methods: Primary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells. Results: Astrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis. Conclusion: We demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes.

There has been substantial progress in the development of regenerative medicine strategies for CNS disorders over the last decade, with progression to early clinical studies for some conditions. However, there are multiple challenges along the translational pipeline, many of which are common across diseases and pertinent to multiple donor cell types. These include defining the point at which the preclinical data are sufficiently compelling to permit progression to the first clinical studies; scaling-up, characterization, quality control and validation of the cell product; design, validation and approval of the surgical device; and operative procedures for safe and effective delivery of cell product to the brain. Furthermore, clinical trials that incorporate principles of efficient design and disease-specific outcomes are urgently needed (particularly for those undertaken in rare diseases, where relatively small cohorts are an additional limiting factor), and all processes must be adaptable in a dynamic regulatory environment. Here we set out the challenges associated with the clinical translation of cell therapy, using Huntington's disease as a specific example, and suggest potential strategies to address these challenges. Huntington's disease presents a clear unmet need, but, importantly, it is an autosomal dominant condition with a readily available gene test, full genetic penetrance and a wide range of associated animal models, which together mean that it is a powerful condition in which to develop principles and test experimental therapeutics. We propose that solving these challenges in Huntington's disease would provide a road map for many other neurological conditions. This white paper represents a consensus opinion emerging from a series of meetings of the international translational platforms Stem Cells for Huntington's Disease and the European Huntington's Disease Network Advanced Therapies Working Group, established to identify the challenges of cell therapy, share experience, develop guidance, and highlight future directions, with the aim to expedite progress towards therapies for clinical benefit in Huntington's disease.Rosser et al. discuss the challenges associated with clinical translation of cell therapies, using Huntington's disease as the primary example. They suggest strategies to address these challenges, based on the consensus view emerging from international workshops and discussion within the platform 'Stem Cells for Huntington's Disease'.

Huntington’s disease is associated with a reactive microglial response and consequent inflammation. To address the role of these cells in disease pathogenesis, we depleted microglia from R6/2 mice, a rapidly progressing model of Huntington’s disease marked by behavioural impairment, mutant huntingtin (mHTT) accumulation, and early death, through colony-stimulating factor 1 receptor inhibition (CSF1Ri) with pexidartinib (PLX3397) for the duration of disease. Although we observed an interferon gene signature in addition to downregulated neuritogenic and synaptic gene pathways with disease, overt inflammation was not evident by microglial morphology or cytokine transcript levels in R6/2 mice. Nonetheless, CSF1Ri-induced microglial elimination reduced or prevented disease-related grip strength and object recognition deficits, mHTT accumulation, astrogliosis, and striatal volume loss, the latter of which was not associated with reductions in cell number but with the extracellular accumulation of chondroitin sulphate proteoglycans (CSPGs)—a primary component of glial scars. A concurrent loss of proteoglycan-containing perineuronal nets was also evident in R6/2 mice, and microglial elimination not only prevented this but also strikingly increased perineuronal nets in the brains of naïve littermates, suggesting a new role for microglia as homeostatic regulators of perineuronal net formation and integrity.

Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Since the reduction of pathogenic mutant HTT messenger RNA is therapeutic, we developed a mutant allele-sensitive CAG

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited antiviral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-λ and Tnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5andCcl19) and cytokine (Ifn-λandTnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease.ImportanceUnderstanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

The complexity of affected brain regions and cell types is a challenge for Huntington’s disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulatorsOLIG1andOLIG2are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identifyPRKCEand Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate forTPK1dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of patients with HD and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex. Of these targets, SG components were enriched, including the SG-nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1-positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of the brains of patients with HD. Intriguingly, we also observed that the SG-associated TAR DNA-binding protein 43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1 granule-positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.

Significance Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by expansion of a polyglutamine repeat within the huntingtin (HTT) protein. A normal function of HTT is that of a scaffold for selective autophagy, a mechanism of protein and organelle degradation by the lysosome required for neuronal health. Here, we show that the inflammatory IκB kinase (IKK) kinase subunit IKKβ may function in vivo to regulate autophagy through direct phosphorylation of HTT at serine 13 and through the activation of autophagy gene expression. IKKβ is required to slow HD behavioral progression and to suppress neurodegeneration and microglial activation in HD transgenic mice. Our work suggests that the early activation of IKK may be protective to activate autophagy, thereby slowing HD progression., Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

DNA damage repair genes are modifiers of disease onset in Huntington's disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find a link between PIAS1 and DNA damage repair pathways. We show that PIAS1 is a component of the transcription-coupled repair complex, that includes the DNA damage end processing enzyme polynucleotide kinase-phosphatase (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knockdown (KD) in HD mice had a normalizing effect on HD transcriptional dysregulation associated with synaptic function and disease-associated transcriptional coexpression modules enriched for DNA damage repair mechanisms as did reduction of PIAS1 in HD iPSC-derived neurons. KD also restored mutant HTT-perturbed enzymatic activity of PNKP and modulated genomic integrity of several transcriptionally normalized genes. The findings here now link SUMO modifying machinery to DNA damage repair responses and transcriptional modulation in neurodegenerative disease.

Huntington’s disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

SUMMARYThe function of huntingtin (HTT) is enigmatic in that the native protein provides neuroprotection while mutant HTT (mHTT) carrying an expanded stretch of glutamines triggers neurotoxicity in Huntington’s disease (HD). We recently reported that HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase and DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP). This complex resolves DNA lesions during transcription to maintain genome integrity, while mHTT impairs the activity of this complex, resulting in DNA lesion accumulation, activating the DNA damage-response in HD. Here we report that HTT forms a DNA repair complex within the mitochondria with mitochondrial RNA polymerase, transcription factors, and PNKP. This complex resolves mitochondrial DNA (mtDNA) lesions to preserve mtDNA integrity and function. Pathogenic mHTT reduces the complex activity, resulting in persistence of mtDNA lesions, impairing mitochondrial function in HD. Restoring the activity of the mtDNA repair complex in a Drosophila model of HD dramatically improves mtDNA integrity, and motor defects.

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease. The strongest genetic risk factor for sporadic AD is carriage of the ε4 allele of the Apolipoprotein E (APOE) gene. Strategies to slow the progression of AD, including dietary interventions, may be modified by the pathogenic effect of this polymorphism. Our objective in this review was to determine the extent and quality of the literature investigating how dietary factors and interventions interact with the APOE ε4 genotype to impact cognitive decline in AD. To that end, we performed a systematic scoping review of published English-language articles involving human subjects. We found evidence suggesting that adherence to a Mediterranean diet may reduce cognitive decline among APOE ε4 carriers, whereas ketogenic agents appear to be ineffective. Diets high in saturated fats may be particularly harmful for APOE ε4 carriers. We identified several topics, including the use of ω-3 fatty acid and antioxidant supplements, for which additional high level evidence is needed.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Answer ALS is a comprehensive multi-omics approach to ALS to ascertain, at a population level, the various clinical-molecular- biochemical subtypes of sporadic ALS. This national program enrolled 1046 ALS and ALS/FTD patients along with a cohort of 100 matched control patients followed longitudinally over at least one year. A smartphone-based app was employed to collect deep clinical data including fine motor activity, speech, breathing and linguistics/cognition. Analytics of the speech patterns revealed a strong correlation between clinical progression indices and speech. In parallel, blood-derived iPS motor neurons were generated from each patient and the cells underwent multi-omics analytics including whole genome sequencing, RNA transcriptomics, ATAC-Seq and proteome along with quality assurance standards. HIPPA compliant cloud data bases were employed to store all data. There are more than 6 billion clinical and molecular data points per patient generated in the program. The program was designed, and patient consented, to be open access to all clinical, biological and molecular data as well as public release of all generated iPS cell lines. A web portal is available to academics as well as commercial researchers. The ultimate intent of this data is for the generation of Integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlying mechanisms of disease including subgroup identification. Overall, this community based clinical and science program provides for the identification of distinct reliably identifiable subgroups among the sporadic and familial patients and the great utility in iPS based approaches to disease pathophysiology and therapy discovery. Although the data is ALS centric, given the large number of both ALS and control data sets, it would also be enormously useful to others studying frontotemporal dementia, Alzheimer’s, Parkinson’s disease and others.

Background The rapid spread of coronavirus disease 2019 (COVID-19) revealed significant constraints in critical care capacity. In anticipation of subsequent waves, reliable prediction of disease severity is essential for critical care capacity management and may enable earlier targeted interventions to improve patient outcomes. The purpose of this study is to develop and externally validate a prognostic model/clinical tool for predicting COVID-19 critical disease at presentation to medical care. Methods This is a retrospective study of a prognostic model for the prediction of COVID-19 critical disease where critical disease was defined as ICU admission, ventilation, and/or death. The derivation cohort was used to develop a multivariable logistic regression model. Covariates included patient comorbidities, presenting vital signs, and laboratory values. Model performance was assessed on the validation cohort by concordance statistics. The model was developed with consecutive patients with COVID-19 who presented to University of California Irvine Medical Center in Orange County, California. External validation was performed with a random sample of patients with COVID-19 at Emory Healthcare in Atlanta, Georgia. Results Of a total 3208 patients tested in the derivation cohort, 9% (299/3028) were positive for COVID-19. Clinical data including past medical history and presenting laboratory values were available for 29% (87/299) of patients (median age, 48 years [range, 21–88 years]; 64% [36/55] male). The most common comorbidities included obesity (37%, 31/87), hypertension (37%, 32/87), and diabetes (24%, 24/87). Critical disease was present in 24% (21/87). After backward stepwise selection, the following factors were associated with greatest increased risk of critical disease: number of comorbidities, body mass index, respiratory rate, white blood cell count, % lymphocytes, serum creatinine, lactate dehydrogenase, high sensitivity troponin I, ferritin, procalcitonin, and C-reactive protein. Of a total of 40 patients in the validation cohort (median age, 60 years [range, 27–88 years]; 55% [22/40] male), critical disease was present in 65% (26/40). Model discrimination in the validation cohort was high (concordance statistic: 0.94, 95% confidence interval 0.87–1.01). A web-based tool was developed to enable clinicians to input patient data and view likelihood of critical disease. Conclusions and relevance We present a model which accurately predicted COVID-19 critical disease risk using comorbidities and presenting vital signs and laboratory values, on derivation and validation cohorts from two different institutions. If further validated on additional cohorts of patients, this model/clinical tool may provide useful prognostication of critical care needs.

BackgroundRecent epidemiological evidence has demonstrated a higher rate of COVID-19 hospitalizations and deaths among minorities. This pattern of race-ethnic disparities emerging throughout the United States raises the question of what social factors may influence spread of a highly transmissible novel coronavirus. The purpose of this study is to describe race-ethnic and socioeconomic disparities associated with COVID-19 in patients in our community in Orange County, California and understand the role of individual-level factors, neighborhood-level factors, and access to care on outcomes.MethodsThis is a case-series of COVID-19 patients from the University of California, Irvine (UCI) across six-weeks between 3/12/2020 and 4/22/2020. Note, California’s shelter-in-place order began on 3/19/2020. Individual-level factors included race-ethnicity status were recorded. Neighborhood-level factors from census tracts included median household income, mean household size, proportion without a college degree, proportion working from home, and proportion without health insurance were also recorded.ResultsA total of 210-patients tested were COVID-19 positive, of which 73.3% (154/210) resided in Orange County. Hispanic/Latinx patients residing in census tracts below the median income demonstrated exponential growth (rate = 55.9%, R2 = 0.9742) during the study period. In addition, there was a significant difference for both race-ethnic (p < 0.001) and income bracket (p = 0.001) distributions prior to and after California’s shelter-in-place. In addition, the percentage of individuals residing in neighborhoods with denser households (p = 0.046), lower levels of college graduation (p < 0.001), health insurance coverage (p = 0.01), and ability to work from home (p < 0.001) significantly increased over the same timeframe.Conclusions and RelevanceOur study examines the race-ethnic disparities in Orange County, CA, and highlights vulnerable populations that are at increased risk for contracting COVID-19. Our descriptive case series illustrates that we also need to consider socioeconomic factors, which ultimately set the stage for biological and social disparities.