Meta-analysis of the amyotrophic lateral sclerosis spectrum uncovers genome instability (original) (raw)
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Amyotrophic Lateral Sclerosis (ALS) is characterised by progressive motor neuron degeneration, but there is marked genetic and clinical heterogeneity1. It has been challenging to identify common ALS mechanisms among this diversity; however, a systematic framework examining motor neurons across the ALS spectrum may reveal unifying insights. Here, we present the most comprehensive compendium of ALS human induced pluripotent stem cell-derived motor neurons (iPSNs) from 429 donors, spanning 10 ALS mutations and sporadic ALS, from 15 datasets, including Answer ALS and NeuroLINCS. Using gold-standard reproducible bioinformatic workflows, we identified that ALS iPSNs show a common increase in the DNA damage response, which is characterised by activation of p53 signalling. The strongest p53 activation was observed in C9orf72 repeat expansions but was also found in TARDBP, FUS and sporadic subgroups. p53 activation was replicated in an ALS postmortem spinal cord cohort of 203 samples, indica...
Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology
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Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, s...
Genome-wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis
2020
ABSTRACTAmyotrophic lateral sclerosis (ALS) is an archetypal complex disease centered on progressive death of motor neurons. Despite heritability estimates of 52%, GWAS studies have discovered only seven genome-wide significant hits, which are relevant to <10% of ALS patients. To increase the power of gene discovery, we integrated motor neuron functional genomics with ALS genetics in a hierarchical Bayesian model called RefMap. Comprehensive transcriptomic and epigenetic profiling of iPSC-derived motor neurons enabled RefMap to systematically fine-map genes and pathways associated with ALS. As a significant extension of the known genetic architecture of ALS, we identified a group of 690 candidate ALS genes, which is enriched with previously discovered risk genes. Extensive conservation, transcriptome and network analyses demonstrated the functional significance of these candidate genes in motor neurons and disease progression. In particular, we observed a genetic convergence on t...
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Amyotrophic lateral sclerosis (ALS) is a severe, progressive and ultimately fatal motor neuron disease caused by a combination of genetic and environmental factors, but its underlying mechanisms are largely unknown. To gain insight into the etiology of ALS, we here conducted genetic network and literature analyses of the top‐ranked findings from six genome‐wide association studies of sporadic ALS (involving 3589 cases and 8577 controls) as well as genes implicated in ALS etiology through other evidence, including familial ALS candidate gene association studies. We integrated these findings into a molecular landscape of ALS that allowed the identification of three main processes that interact with each other and are crucial to maintain axonal functionality, especially of the long axons of motor neurons, i.e. (1) Rho‐GTPase signaling; (2) signaling involving the three regulatory molecules estradiol, folate, and methionine; and (3) ribonucleoprotein granule functioning and axonal trans...
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Despite clear therapeutic potential, the mechanisms that confer differential neuronal sensitivity are not well understood. During Amyotrophic Lateral Sclerosis (ALS), sensitive spinal motor neurons (SpMN) die while a subset of rostral cranial motor neurons (CrMN) survive. In this work, we optimized a protocol to differentiate CrMNs and SpMNs from human induced pluripotent stem cells (iPSCs) by direct programming and positional patterning. Human iCrMNs are more resistant than iSpMNs to proteotoxic stress and rely on the proteasome to maintain proteostasis. iCrMNs better prevent mislocalization of TDP43 from the nucleus, a hallmark of ALS progression. iSpMNs contain more splicing defects than iCrMNs in response to ALS-related stress with genes involved in splicing and proteostasis maintenance. Therefore, iCrMNs resist ALS at two levels, preventing protein accumulation and reducing splicing defects in response to TDP43 nuclear depletion. Thus, ALS-sensitive iSpMNs appear to enter a dow...
Stem Cell Reports, 2016
Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq datasets revealed aberrant gene expression and/or splicing pattern in FALS MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders.
Molecular Taxonomy of Sporadic Amyotrophic Lateral Sclerosis Using Disease-Associated Genes
Frontiers in Neurology, 2017
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Despite intensive research, the origin and progression of ALS remain largely unknown, suggesting that the traditional clinical diagnosis and treatment strategies might not be adequate to completely capture the molecular complexity underlying the disease. In our previous work, comprehensive genomic profiling of 41 motor cortex samples enabled to discriminate control from sporadic ALS patients and segregated these latter into two distinct subgroups, each associated with different deregulated genes and pathways. Interestingly, some deregulated genes in sporadic ALS were previously associated with familiar ALS, indicating shared pathogenic mechanisms between the two forms of disease. In this, we performed cluster analysis on the same whole-genome expression profiles using a restricted (203) subset of genes extensively implicated in monogenic forms of ALS. Surprisingly, this short and unbiased gene list was sufficiently representative to allow the accurate separation of SALS patients from controls and the stratification of SALS patients into two molecularly distinct subgroups. Overall, our findings support the existence of a molecular taxonomy for ALS and represent a further step toward the establishment of a molecular-based diagnosis and patient-tailored therapies.
Scientific Reports, 2016
The aim of the present study is to investigate the molecular pathways underlying amyotrophic lateral sclerosis (ALS) pathogenesis within the peripheral nervous system. We analyzed gene expression changes in human motor nerve diagnostic biopsies obtained from eight ALS patients and seven patients affected by motor neuropathy as controls. An integrated transcriptomics and system biology approach was employed. We identified alterations in the expression of 815 genes, with 529 up-regulated and 286 down-regulated in ALS patients. Up-regulated genes clustered around biological process involving RNA processing and protein metabolisms. We observed a significant enrichment of up-regulated small nucleolar RNA transcripts (p = 2.68*10-11) and genes related to endoplasmic reticulum unfolded protein response and chaperone activity. We found a significant down-regulation in ALS of genes related to the glutamate metabolism. Interestingly, a network analysis highlighted HDAC2, belonging to the histone deacetylase family, as the most interacting node. While so far gene expression studies in human ALS have been performed in postmortem tissues, here specimens were obtained from biopsy at an early phase of the disease, making these results new in the field of ALS research and therefore appealing for gene discovery studies. Amyotrophic lateral sclerosis (ALS) is the most common and severe form within the group of motor neuron diseases (MND), characterized by degeneration of both upper and lower motor neurons, leading to death two to five years after diagnosis 1,2. While most ALS cases apparently occur sporadically (sALS), up to 10% have an affected relative and are considered familial (fALS) cases. In spite of recent advances in unraveling the genetic etiology of ALS 3 , mechanism/s of disease initiation and progression still remain elusive, even if protein misfolding and aggregation, dysregulation of RNA processing, proteasome impairment, neuro-inflammation, excitotoxicity, cytoskeleton and mitochondrial dysfunctions have been proposed 4,5. It has been recently demonstrated that motor neuron cell death in ALS is profoundly influenced by neighboring non-neuronal cells, including glial cells, thus implicating a non-cell autonomous mechanism in disease pathogenesis 5,6. Neurons are extremely polarized cells and neuronal cell body size is exceeded by several orders of magnitude by the length of axons, which represent up
Scientific Reports, 2019
Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specific loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification. To our knowledge, this is the first comprehensive "omics" analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss and degeneration of motor neurons in both the motor cortex, brainstem and spinal cord, and is usually fatal due to respiratory failure within 3-5 years of onset 1. The disease has an incidence of 2.6 per 100,000 individuals-years and prevalence rates of around 6-7/100,000 in Europe, making it the most common adult-onset motor neuron disease 2. About 5-10% of ALS cases show a family history (FALS), while the remainder of cases are classified as sporadic (SALS), and are probably associated to a polygenic and multifactorial etiology 3-5. The remarkable advances in genome technologies over the last years have led to a huge progress in deciphering the genes and pathways involved in ALS pathogenesis. From the discovery of the first ALS-associated gene SOD1, several candidate-gene or genome-wide association studies (GWAS) have identified multiple single-nucleotide polymorphisms (SNPs) affecting potentially ALS-associated genes, including C9orf72, TDP43, FUS, MATR3, UBQLN2, VCP and OPTN 6-9. In this context, a recent large-scale genome-wide association study identified a common missense variant and several rare loss-of-function (LOF) mutations within the microtubule motor 1 institute of neurological Sciences, italian national Research council, catania, italy.