The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.

Recent advances in the genetics of familial and sporadic ALS.

ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.

Transcriptomics of Human Brain Tissue in Parkinson's Disease: a Comparison of Bulk and Single-cell RNA Sequencing.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease leading to motor dysfunction and, in some cases, dementia. Transcriptome analysis is one promising approach for characterizing PD and other neurodegenerative disorders by informing how specific disease events influence gene expression and contribute to pathogenesis. With the emergence of single-cell and single-nucleus RNA sequencing (scnRNA-seq) technologies, the transcriptional landscape of neurodegenerative diseases can now be described at the cellular level. As the application of scnRNA-seq is becoming routine, it calls to question how results at a single-cell resolution compare to those obtained from RNA sequencing of whole tissues (bulk RNA-seq), whether the findings are compatible, and how the assays are complimentary for unraveling the elusive transcriptional changes that drive neurodegenerative disease. Herein, we review the studies that have leveraged RNA-seq technologies to investigate PD. Through the integration of bulk and scnRNA-seq findings from human, post-mortem brain tissue, we use the PD literature as a case study to evaluate the compatibility of the results generated from each assay and demonstrate the complementarity of the sequencing technologies. Finally, through the lens of the PD transcriptomic literature, we evaluate the current feasibility of bulk and scnRNA-seq technologies to illustrate the necessity of both technologies for achieving a comprehensive insight into the mechanism by which gene expression promotes neurodegenerative disease. We conclude that the continued application of both assays will provide the greatest insight into neurodegenerative disease pathology, providing both cell-specific and whole-tissue level information.

Identification of gene fusions associated with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Recent findings demonstrate that in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. Gene fusion events have been studied extensively in cancer; however, they have not been thoroughly investigated in ALS. The aim of this study was to determine whether gene fusions are present in ALS. METHODS: Gene fusions were identified using STAR Fusion v1.10.0 software in bulk RNA-Seq data from human postmortem samples from publicly available data sets from Target ALS and the New York Genome Center ALS Consortium. RESULTS: We report the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significantly greater number of unique gene fusions in ALS compared to controls. Lastly, we identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases. DISCUSSION: Collectively, our findings reveal an enrichment of gene fusions in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.

KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Rare-variant and polygenic analyses of amyotrophic lateral sclerosis in the French-Canadian genome.

PURPOSE: The genetic etiology of amyotrophic lateral sclerosis (ALS) includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both. METHODS: 335 ALS cases and 356 controls from Québec, Canada were concurrently tested by microarray genotyping and targeted sequencing of ALS genes known at the time of study inception. ALS genome-wide association studies summary statistics were used to estimate an ALS polygenic risk score (PRS). Cases and controls were subdivided into rare-variant heterozygotes and non-heterozygotes. RESULTS: Risk for ALS was significantly associated with PRS and rare variants independently in a logistic regression model. Although ALS PRS predicted a small amount of ALS risk overall, the effect was most pronounced between ALS cases and controls that were not heterozygous for a rare variant in the ALS genes surveyed. CONCLUSION: Both PRS and rare variants in ALS genes impact risk for ALS. PRS for ALS is most informative when rare variants are not observed in ALS genes.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes.

Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3864 individuals with ALS and 7839 controls) and Project MinE ALS Sequencing Consortium (4366 individuals with ALS and 1832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes. The two sequencing datasets were interrogated for missense variants in the 24 genes, and variants were annotated with gnomAD minor allele frequencies, ClinVar pathogenicity classifications, protein sequence features including Uniprot functional site annotations, and PhosphoSitePlus post-translational modification site annotations, structural features from AlphaFold predicted monomeric 3D structures, and transcriptomic expression levels from Genotype-Tissue Expression. We then applied missense variant enrichment and gene-burden testing following binning of variation based on the selected proteomic and transcriptomic features to identify those most relevant to pathogenicity in ALS-associated genes. Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in ß-sheets and α-helices, as well as in core, buried or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and regions of interest are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses and identified individual genes were indeed driving certain enrichment signals. A case study is presented for SOD1 to demonstrate proof-of-concept of how enriched features may aid in defining variant pathogenicity. Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.

Rare neurovascular genetic and imaging markers across neurodegenerative diseases.

INTRODUCTION: Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status. METHODS: The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1). RESULTS: NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood. DISCUSSION: Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

Association of Dual-Task Gait Cost and White Matter Hyperintensity Burden Poststroke: Results From the ONDRI.

BACKGROUND: Acute change in gait speed while performing a mental task [dual-task gait cost (DTC)], and hyperintensity magnetic resonance imaging signals in white matter are both important disability predictors in older individuals with history of stroke (poststroke). It is still unclear, however, whether DTC is associated with overall hyperintensity volume from specific major brain regions in poststroke. METHODS: This is a cohort study with a total of 123 older (69 ± 7 years of age) participants with history of stroke were included from the Ontario Neurodegenerative Disease Research Initiative. Participants were clinically assessed and had gait performance assessed under single- and dual-task conditions. Structural neuroimaging data were analyzed to measure both, white matter hyperintensity (WMH) and normal appearing volumes. Percentage of WMH volume in frontal, parietal, occipital, and temporal lobes as well as subcortical hyperintensities in basal ganglia + thalamus were the main outcomes. Multivariate models investigated associations between DTC and hyperintensity volumes, adjusted for age, sex, years of education, global cognition, vascular risk factors, APOE4 genotype, residual sensorimotor symptoms from previous stroke and brain volume. RESULTS: There was a significant positive global linear association between DTC and hyperintensity burden (adjusted Wilks' λ = .87, P = .01). Amongst all WMH volumes, hyperintensity burden from basal ganglia + thalamus provided the most significant contribution to the global association (adjusted ß = .008, η2 = .03; P = .04), independently of brain atrophy. CONCLUSIONS: In poststroke, increased DTC may be an indicator of larger white matter damages, specifically in subcortical regions, which can potentially affect the overall cognitive processing and decrease gait automaticity by increasing the cortical control over patients' locomotion.

MTSviewer: A database to visualize mitochondrial targeting sequences, cleavage sites, and mutations on protein structures.

Mitochondrial dysfunction is implicated in a wide array of human diseases ranging from neurodegenerative disorders to cardiovascular defects. The coordinated localization and import of proteins into mitochondria are essential processes that ensure mitochondrial homeostasis. The localization and import of most mitochondrial proteins are driven by N-terminal mitochondrial targeting sequences (MTS's), which interact with import machinery and are removed by the mitochondrial processing peptidase (MPP). The recent discovery of internal MTS's-those which are distributed throughout a protein and act as import regulators or secondary MPP cleavage sites-has expanded the role of both MTS's and MPP beyond conventional N-terminal regulatory pathways. Still, the global mutational landscape of MTS's remains poorly characterized, both from genetic and structural perspectives. To this end, we have integrated a variety of tools into one harmonized R/Shiny database called MTSviewer (https://neurobioinfo.github.io/MTSvieweR/), which combines MTS predictions, cleavage sites, genetic variants, pathogenicity predictions, and N-terminomics data with structural visualization using AlphaFold models of human and yeast mitochondrial proteomes. Using MTSviewer, we profiled all MTS-containing proteins across human and yeast mitochondrial proteomes and provide multiple case studies to highlight the utility of this database.

Clinical testing panels for ALS: global distribution, consistency, and challenges.

Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families.

APOE alleles are associated with sex-specific structural differences in brain regions affected in Alzheimer's disease and related dementia.

Alzheimer's disease is marked by intracellular tau aggregates in the medial temporal lobe (MTL) and extracellular amyloid aggregates in the default network (DN). Here, we examined codependent structural variations between the MTL's most vulnerable structure, the hippocampus (HC), and the DN at subregion resolution in individuals with Alzheimer's disease and related dementia (ADRD). By leveraging the power of the approximately 40,000 participants of the UK Biobank cohort, we assessed impacts from the protective APOE ɛ2 and the deleterious APOE ɛ4 Alzheimer's disease alleles on these structural relationships. We demonstrate ɛ2 and ɛ4 genotype effects on the inter-individual expression of HC-DN co-variation structural patterns at the population level. Across these HC-DN signatures, recurrent deviations in the CA1, CA2/3, molecular layer, fornix's fimbria, and their cortical partners related to ADRD risk. Analyses of the rich phenotypic profiles in the UK Biobank cohort further revealed male-specific HC-DN associations with air pollution and female-specific associations with cardiovascular traits. We also showed that APOE ɛ2/2 interacts preferentially with HC-DN co-variation patterns in estimating social lifestyle in males and physical activity in females. Our structural, genetic, and phenotypic analyses in this large epidemiological cohort reinvigorate the often-neglected interplay between APOE ɛ2 dosage and sex and link APOE alleles to inter-individual brain structural differences indicative of ADRD familial risk.

Questioning the Association of the STMN2 Dinucleotide Repeat With Amyotrophic Lateral Sclerosis.

Objectives: Recently, the number of dinucleotide CA repeats in an intron of the STMN2 gene was reported to be associated with an increased risk for amyotrophic lateral sclerosis (ALS). Therefore, we sought to replicate this observation in an independent group of ALS patients and a much larger control group. Methods: Here, we used whole-genome sequencing and tested the STMN2 CA repeat in a case-control cohort of the European genetic background and in genomes from various populations in the gnomAD cohort to attempt to replicate this proposed association. Results: We find that repeats well above the previously reported pathogenic threshold of 19 are commonly observed in unaffected individuals across different populations. Furthermore, we did not observe an association between longer STMN2 CA repeats and ALS phenotype. Discussion: In summary, our results do not support a role of STMN2 CA repeats toward ALS risk. As TDP-43 aggregation is central to ALS pathogenesis, lowered expression of STMN2 could be used as a biomarker for ALS. Therefore, a variant associated both with the risk for ALS and the level of STMN2 expression would be clinically useful. However, for a variant to be actionable, it must be strongly replicated in independent cohorts and exceed the rigorous statistical thresholds applied.

Lack of association of TP73 with amyotrophic lateral sclerosis in a large cohort of cases.

A recent study suggested an association between rare, non-synonymous variants in the gene encoding tumor protein p73 (TP73) and amyotrophic lateral sclerosis (ALS) - a progressive, fatal neurodegenerative disease. The original association was based on a case-control analysis with relatively small sample size. While functional data were presented to substantiate these claims, it remains unclear whether the results demonstrate clinical significance; additionally, the modelled null alleles had been recently reported to cause a severe pediatric disorder characterized by impaired mucociliary clearance and lissencephaly. Here, we aimed to replicate the proposed genetic association between TP73 and ALS using the two largest publicly available ALS sequencing datasets as hosted by the ALS Knowledge Portal (n = 3864 cases and n = 7839 controls) and the Project MinE ALS browser (n = 4366 cases and n = 1832 controls) for a total of 8230 ALS cases and 9671 controls. We did not observe an enrichment of rare, protein-coding variants in the ALS cases and surprisingly identified a relatively large number of controls carrying rare, non-synonymous variants in TP73 (n = 65). Based on these results we conclude that TP73 most likely does not predispose to ALS.

DnaJC7 in Amyotrophic Lateral Sclerosis.

Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin-proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones' machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in DNAJC7 contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS.

Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS.

The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3'UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3'UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases.

Expanding the phenotypic and molecular spectrum of NFS1-related disorders that cause functional deficiencies in mitochondrial and cytosolic iron-sulfur cluster containing enzymes.

Iron-sulfur cluster proteins are involved in critical functions for gene expression regulation and mitochondrial bioenergetics including the oxidative phosphorylation system. The c.215G>A p.(Arg72Gln) variant in NFS1 has been previously reported to cause infantile mitochondrial complex II and III deficiency. We describe three additional unrelated patients with the same missense variant. Two infants with the same homozygous variant presented with hypotonia, weakness and lactic acidosis, and one patient with compound heterozygous p.(Arg72Gln) and p.(Arg412His) variants presented as a young adult with gastrointestinal symptoms and fatigue. Skeletal muscle biopsy from patients 1 and 3 showed abnormal mitochondrial morphology, and functional analyses demonstrated decreased activity in respiratory chain complex II and variably in complexes I and III. We found decreased mitochondrial and cytosolic aconitase activities but only mildly affected lipoylation of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase enzymes. Our studies expand the phenotypic spectrum and provide further evidence for the pathogenicity and functional sequelae of NFS1-related disorders with disturbances in both mitochondrial and cytosolic iron-sulfur cluster containing enzymes.

Sex-stratified RNA-seq analysis reveals traumatic brain injury-induced transcriptional changes in the female hippocampus conducive to dementia.

Introduction: Traumatic brain injury (TBI), resulting from a violent force that causes functional changes in the brain, is the foremost environmental risk factor for developing dementia. While previous studies have identified specific candidate genes that may instigate worse outcomes following TBI when mutated, TBI-induced changes in gene expression conducive to dementia are critically understudied. Additionally, biological sex seemingly influences TBI outcomes, but the discrepancies in post-TBI gene expression leading to progressive neurodegeneration between the sexes have yet to be investigated. Methods: We conducted a whole-genome RNA sequencing analysis of post-mortem brain tissue from the parietal neocortex, temporal neocortex, frontal white matter, and hippocampus of 107 donors characterized by the Aging, Dementia, and Traumatic Brain Injury Project. Our analysis was sex-stratified and compared gene expression patterns between TBI donors and controls, a subset of which presented with dementia. Results: We report three candidate gene modules from the female hippocampus whose expression correlated with dementia in female TBI donors. Enrichment analyses revealed that the candidate modules were notably enriched in cardiac processes and the immune-inflammatory response, among other biological processes. In addition, multiple candidate module genes showed a significant positive correlation with hippocampal concentrations of monocyte chemoattractant protein-1 in females with post-TBI dementia, which has been previously described as a potential biomarker for TBI and susceptibility to post-injury dementia. We concurrently examined the expression profiles of these candidate modules in the hippocampus of males with TBI and found no apparent indicator that the identified candidate modules contribute to post-TBI dementia in males. Discussion: Herein, we present the first sex-stratified RNA sequencing analysis of TBI-induced changes within the transcriptome that may be conducive to dementia. This work contributes to our current understanding of the pathophysiological link between TBI and dementia and emphasizes the growing interest in sex as a biological variable affecting TBI outcomes.