Progress in Amyotrophic Lateral Sclerosis Gene Discovery

Smukowski, Samuel N.; Maioli, Heather; Latimer, Caitlin S.; Bird, Thomas D.; Jayadev, Suman; Valdmanis, Paul N.

doi:10.1212/nxg.0000000000000669

Cited by 18 publications

(15 citation statements)

References 65 publications

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“…It was not until the introduction of largescale, high-throughput genotyping techniques that ALS genetics progressed. 19 Initially, this was through GWAS that allow the screening of common genetic variation in large populations. GWAS makes use of high throughput genotyping and linkage disequilibrium (LD) to screen the genome for common variants (singlenucleotide polymorphisms, SNPs) associated with the trait of interest.…”

Section: Genetic Association Studies In Alsmentioning

confidence: 99%

“…Although state-of-the-art at the time, candidate gene approaches were inherently vulnerable to bias and did not significantly further our understanding of ALS. It was not until the introduction of large-scale, high-throughput genotyping techniques that ALS genetics progressed 19…”

Section: Genetic Association Studies In Alsmentioning

confidence: 99%

“…The latest and largest GWAS, to date, with 29 612 cases and 122 656 controls, identified 15 risk loci, 7 of which had not been previously described 13. Through the use of novel sequencing techniques, over 60 different genes have been identified for ALS and combined have demonstrated a monogenetic basis in ±70% of FALS cases and in 10% of SALS 19 21. Genetic mutations which are known to be monogenetic are also detected though GWAS 13.…”

Section: Genetic Association Studies In Alsmentioning

confidence: 99%

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UNC13Ain amyotrophic lateral sclerosis: from genetic association to therapeutic target

Willemse

Harley

Eijk

et al. 2023

J Neurol Neurosurg Psychiatry

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in theUNC13Agene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants inUNC13Alead to the inclusion of a cryptic exon inUNC13Amessenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion ofUNC13Aleads to impaired neurotransmission. Recent discoveries have identifiedUNC13Aas a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate inUNC13Acases now underway and future approaches with antisense oligonucleotides currently under consideration. ConsideringUNC13Ais a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery ofUNC13Aas a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.

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Section: Genetic Association Studies In Alsmentioning

confidence: 99%

Section: Genetic Association Studies In Alsmentioning

confidence: 99%

Section: Genetic Association Studies In Alsmentioning

confidence: 99%

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UNC13Ain amyotrophic lateral sclerosis: from genetic association to therapeutic target

Willemse

Harley

Eijk

et al. 2023

J Neurol Neurosurg Psychiatry

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“…ALS is a complex disease because it has been linked to multiple aggregating proteins which include chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase 1 (SOD1), tar-DNA binding protein 43 (TDP-43), rho guanine nucleotide exchange factor (RGNEF), phosphorylated high molecular weight neurofilament protein (pNFH), fused in sarcoma (FUS), and others [ 7 ]. To date, over 45 genes have been found linked to ALS pathology [ 8 ], but there is still an inadequate understanding of the disease mechanisms. Efforts involving the discovery and validation of genes causal to ALS pathology have yielded critical insights into relevant cellular mechanisms that lead to neurodegeneration such as autophagy defects, cytoskeleton alterations, endoplasmic reticulum stress, nucleocytoplasmic transport, protein homeostasis, and RNA metabolism [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis

Fatoki

Chukwuejim

Udenigwe

et al. 2023

IJMS

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Amyotrophic lateral sclerosis (ALS) is regarded as a fatal neurodegenerative disease that is featured by progressive damage of the upper and lower motor neurons. To date, over 45 genes have been found to be connected with ALS pathology. The aim of this work was to computationally identify unique sets of protein hydrolysate peptides that could serve as therapeutic agents against ALS. Computational methods which include target prediction, protein-protein interaction, and peptide-protein molecular docking were used. The results showed that the network of critical ALS-associated genes consists of ATG16L2, SCFD1, VAC15, VEGFA, KEAP1, KIF5A, FIG4, TUBA4A, SIGMAR1, SETX, ANXA11, HNRNPL, NEK1, C9orf72, VCP, RPSA, ATP5B, and SOD1 together with predicted kinases such as AKT1, CDK4, DNAPK, MAPK14, and ERK2 in addition to transcription factors such as MYC, RELA, ZMIZ1, EGR1, TRIM28, and FOXA2. The identified molecular targets of the peptides that support multi-metabolic components in ALS pathogenesis include cyclooxygenase-2, angiotensin I-converting enzyme, dipeptidyl peptidase IV, X-linked inhibitor of apoptosis protein 3, and endothelin receptor ET-A. Overall, the results showed that AGL, APL, AVK, IIW, PVI, and VAY peptides are promising candidates for further study. Future work would be needed to validate the therapeutic properties of these hydrolysate peptides by in vitro and in vivo approaches.

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“…In recent years, genome-wide association studies (GWAS) have enabled the discovery of numerous associations of single nucleotide polymorphisms (SNPs) to complex diseases, including ALS. Previous genetic inheritance and genome-wide studies have identified numerous variants mapped to 46 genes as monogenic causes of ALS [ 7 , 8 , 9 , 10 , 11 , 12 ]. In European ancestry populations, the most common monogenic cause is the intronic hexanucleotide GGGGCC (G4C2) repeat expansion (HRE) in the C9ORF72 gene [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS

Vasilopoulou

McDaid-McCloskey

McCluskey

et al. 2023

IJMS

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Amyotrophic lateral sclerosis (ALS) is a fatal late-onset motor neuron disease characterized by the loss of the upper and lower motor neurons. Our understanding of the molecular basis of ALS pathology remains elusive, complicating the development of efficient treatment. Gene-set analyses of genome-wide data have offered insight into the biological processes and pathways of complex diseases and can suggest new hypotheses regarding causal mechanisms. Our aim in this study was to identify and explore biological pathways and other gene sets having genomic association to ALS. Two cohorts of genomic data from the dbGaP repository were combined: (a) the largest available ALS individual-level genotype dataset (N = 12,319), and (b) a similarly sized control cohort (N = 13,210). Following comprehensive quality control pipelines, imputation and meta-analysis, we assembled a large European descent ALS-control cohort of 9244 ALS cases and 12,795 healthy controls represented by genetic variants of 19,242 genes. Multi-marker analysis of genomic annotation (MAGMA) gene-set analysis was applied to an extensive collection of 31,454 gene sets from the molecular signatures database (MSigDB). Statistically significant associations were observed for gene sets related to immune response, apoptosis, lipid metabolism, neuron differentiation, muscle cell function, synaptic plasticity and development. We also report novel interactions between gene sets, suggestive of mechanistic overlaps. A manual meta-categorization and enrichment mapping approach is used to explore the overlap of gene membership between significant gene sets, revealing a number of shared mechanisms.

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Progress in Amyotrophic Lateral Sclerosis Gene Discovery

Cited by 18 publications

References 65 publications

UNC13Ain amyotrophic lateral sclerosis: from genetic association to therapeutic target

UNC13Ain amyotrophic lateral sclerosis: from genetic association to therapeutic target

In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis

Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS

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