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1.
Proc Natl Acad Sci U S A ; 121(27): e2406734121, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38913897

RESUMEN

The Merovingian period (5th to 8th cc AD) was a time of demographic, socioeconomic, cultural, and political realignment in Western Europe. Here, we report the whole-genome shotgun sequence data of 30 human skeletal remains from a coastal Late Merovingian site of Koksijde (675 to 750 AD), alongside 18 remains from two Early to Late Medieval sites in present-day Flanders, Belgium. We find two distinct ancestries, one shared with Early Medieval England and the Netherlands, while the other, minor component, reflecting likely continental Gaulish ancestry. Kinship analyses identified no large pedigrees characteristic to elite burials revealing instead a high modularity of distant relationships among individuals of the main ancestry group. In contrast, individuals with >90% Gaulish ancestry had no kinship links among sampled individuals. Evidence for population structure and major differences in the extent of Gaulish ancestry in the main group, including in a mother-daughter pair, suggests ongoing admixture in the community at the time of their burial. The isotopic and genetic evidence combined supports a model by which the burials, representing an established coastal nonelite community, had incorporated migrants from inland populations. The main group of burials at Koksijde shows an abundance of >5 cM long shared allelic intervals with the High Medieval site nearby, implying long-term continuity and suggesting that similarly to Britain, the Early Medieval ancestry shifts left a significant and long-lasting impact on the genetic makeup of the Flemish population. We find substantial allele frequency differences between the two ancestry groups in pigmentation and diet-associated variants, including those linked with lactase persistence, likely reflecting ancestry change rather than local adaptation.


Asunto(s)
Linaje , Humanos , Historia Medieval , Bélgica , Entierro/historia , Genética de Población/métodos , Femenino , Masculino , ADN Antiguo/análisis , Inglaterra , Migración Humana , Arqueología , Países Bajos , Genoma Humano
2.
EMBO J ; 40(7): e106177, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33694180

RESUMEN

TDP-43 is the major component of pathological inclusions in most ALS patients and in up to 50% of patients with frontotemporal dementia (FTD). Heterozygous missense mutations in TARDBP, the gene encoding TDP-43, are one of the common causes of familial ALS. In this study, we investigate TDP-43 protein behavior in induced pluripotent stem cell (iPSC)-derived motor neurons from three ALS patients with different TARDBP mutations, three healthy controls and an isogenic control. TARDPB mutations induce several TDP-43 changes in spinal motor neurons, including cytoplasmic mislocalization and accumulation of insoluble TDP-43, C-terminal fragments, and phospho-TDP-43. By generating iPSC lines with allele-specific tagging of TDP-43, we find that mutant TDP-43 initiates the observed disease phenotypes and has an altered interactome as indicated by mass spectrometry. Our findings also indicate that TDP-43 proteinopathy results in a defect in mitochondrial transport. Lastly, we show that pharmacological inhibition of histone deacetylase 6 (HDAC6) restores the observed TDP-43 pathologies and the axonal mitochondrial motility, suggesting that HDAC6 inhibition may be an interesting therapeutic target for neurodegenerative disorders linked to TDP-43 pathology.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Transporte Axonal , Proteínas de Unión al ADN/genética , Histona Desacetilasa 6/metabolismo , Neuronas Motoras/metabolismo , Esclerosis Amiotrófica Lateral/genética , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Células Madre Pluripotentes Inducidas/citología , Mitocondrias/metabolismo , Neuronas Motoras/citología , Neuronas Motoras/efectos de los fármacos , Mutación Missense
3.
N Engl J Med ; 387(12): 1099-1110, 2022 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-36129998

RESUMEN

BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).


Asunto(s)
Esclerosis Amiotrófica Lateral , Oligonucleótidos Antisentido , Superóxido Dismutasa-1 , Adulto , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Método Doble Ciego , Humanos , Inyecciones Espinales , Proteínas de Neurofilamentos/sangre , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/uso terapéutico , Recuperación de la Función/efectos de los fármacos , Superóxido Dismutasa-1/líquido cefalorraquídeo , Superóxido Dismutasa-1/genética
4.
Brain ; 147(9): 3113-3130, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-38743588

RESUMEN

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 Mb tandem duplication of chromosome 17 harbouring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To obtain better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication in cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing (RNA-seq) on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient-derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was downregulated in a dose-dependent manner throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signalling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane owing to an alteration in the lipid composition, which might ultimately lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of patients with CMT1A.


Asunto(s)
Membrana Celular , Enfermedad de Charcot-Marie-Tooth , Homeostasis , Células Madre Pluripotentes Inducidas , Metabolismo de los Lípidos , Proteínas de la Mielina , Células de Schwann , Animales , Humanos , Ratones , Membrana Celular/metabolismo , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Duplicación de Gen , Homeostasis/fisiología , Células Madre Pluripotentes Inducidas/metabolismo , Metabolismo de los Lípidos/fisiología , Proteínas de la Mielina/metabolismo , Proteínas de la Mielina/genética , Células de Schwann/metabolismo , Nervio Ciático/metabolismo
5.
Mol Cell ; 65(6): 1044-1055.e5, 2017 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-28306503

RESUMEN

Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2α phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Arginina/metabolismo , Gránulos Citoplasmáticos/metabolismo , Dipéptidos/metabolismo , Proteínas Intrínsecamente Desordenadas/metabolismo , Proteínas/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Arginina/química , Proteína C9orf72 , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Gránulos Citoplasmáticos/patología , ADN Helicasas , Dipéptidos/química , Factor 2 Eucariótico de Iniciación/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Células HeLa , Humanos , Proteínas Intrínsecamente Desordenadas/química , Gotas Lipídicas/metabolismo , Fosforilación , Proteínas de Unión a Poli-ADP-Ribosa , Dominios Proteicos , Proteínas/química , ARN/metabolismo , ARN Helicasas , Proteínas con Motivos de Reconocimiento de ARN , Factores de Tiempo , Transfección
6.
Curr Opin Neurol ; 37(5): 560-569, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38967083

RESUMEN

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) has a strong genetic basis, but the genetic landscape of ALS appears to be complex. The purpose of this article is to review recent developments in the genetics of ALS. RECENT FINDINGS: Large-scale genetic studies have uncovered more than 40 genes contributing to ALS susceptibility. Both rare variants with variable effect size and more common variants with small effect size have been identified. The most common ALS genes are C9orf72 , SOD1 , TARDBP and FUS . Some of the causative genes of ALS are shared with frontotemporal dementia, confirming the molecular link between both diseases. Access to diagnostic gene testing for ALS has to improve, as effective gene silencing therapies for some genetic subtypes of ALS are emerging, but there is no consensus about which genes to test for. SUMMARY: Our knowledge about the genetic basis of ALS has improved and the first effective gene silencing therapies for specific genetic subtypes of ALS are underway. These therapeutic advances underline the need for better access to gene testing for people with ALS. Further research is needed to further map the genetic heterogeneity of ALS and to establish the best strategy for gene testing in a clinical setting.


Asunto(s)
Esclerosis Amiotrófica Lateral , Proteína C9orf72 , Predisposición Genética a la Enfermedad , Proteína FUS de Unión a ARN , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/diagnóstico , Proteína C9orf72/genética , Predisposición Genética a la Enfermedad/genética , Proteína FUS de Unión a ARN/genética , Superóxido Dismutasa-1/genética , Superóxido Dismutasa/genética , Proteínas/genética , Proteínas de Unión al ADN/genética , Pruebas Genéticas
7.
Acta Neuropathol ; 147(1): 41, 2024 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-38363426

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of the cases. Understanding the mechanisms by which mutant FUS becomes toxic to neurons can provide insight into the pathogenesis of both familial and sporadic ALS. We have previously observed that overexpression of wild-type or ALS-mutant FUS in Drosophila motor neurons is toxic, which allowed us to screen for novel genetic modifiers of the disease. Using a genome-wide screening approach, we identified Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALS. Loss of function or pharmacological inhibition of either protein rescued FUS-associated lethality in Drosophila. Consistent with a conserved role in disease pathogenesis, pharmacological inhibition of both proteins rescued disease-relevant phenotypes, including mitochondrial trafficking defects and neuromuscular junction failure, in patient iPSC-derived spinal motor neurons (iPSC-sMNs). In FUS-ALS flies, mice, and human iPSC-sMNs, we observed reduced GSK3 inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3 hyperactivity. Furthermore, we found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation. GSK3 has previously been linked to kinesin-1 hyperphosphorylation. We observed this in both flies and iPSC-sMNs, and we rescued this hyperphosphorylation by inhibiting GSK3 or PP2A. Moreover, increasing the level of kinesin-1 expression in our Drosophila model strongly rescued toxicity, confirming the relevance of kinesin-1 hyperphosphorylation. Our data provide in vivo evidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3, and kinesin-1, that may be central to the pathogenesis of FUS-ALS and sporadic forms of the disease.


Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Animales , Humanos , Ratones , Esclerosis Amiotrófica Lateral/patología , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Enfermedades Neurodegenerativas/patología , Cinesinas/genética , Cinesinas/metabolismo , Neuronas Motoras/metabolismo , Drosophila/genética , Drosophila/metabolismo , Mutación/genética
8.
Acta Neuropathol ; 148(1): 55, 2024 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-39424714

RESUMEN

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aß) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.


Asunto(s)
Enfermedad de Alzheimer , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Predisposición Genética a la Enfermedad , Apolipoproteínas E/genética , Ovillos Neurofibrilares/patología , Ovillos Neurofibrilares/genética , Estudio de Asociación del Genoma Completo , Proteínas tau/genética , Placa Amiloide/patología , Placa Amiloide/genética , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
9.
Eur J Neurol ; 31(6): e16264, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38470068

RESUMEN

BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management. CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.


Asunto(s)
Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/terapia , Humanos , Europa (Continente) , Neurología/normas , Neurología/métodos , Enfermedades Neuromusculares/terapia
10.
Brain ; 146(9): 3770-3782, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36883643

RESUMEN

Amyotrophic lateral sclerosis is a fatal and incurable neurodegenerative disease that mainly affects the neurons of the motor system. Despite the increasing understanding of its genetic components, their biological meanings are still poorly understood. Indeed, it is still not clear to which extent the pathological features associated with amyotrophic lateral sclerosis are commonly shared by the different genes causally linked to this disorder. To address this point, we combined multiomics analysis covering the transcriptional, epigenetic and mutational aspects of heterogenous human induced pluripotent stem cell-derived C9orf72-, TARDBP-, SOD1- and FUS-mutant motor neurons as well as datasets from patients' biopsies. We identified a common signature, converging towards increased stress and synaptic abnormalities, which reflects a unifying transcriptional program in amyotrophic lateral sclerosis despite the specific profiles due to the underlying pathogenic gene. In addition, whole genome bisulphite sequencing linked the altered gene expression observed in mutant cells to their methylation profile, highlighting deep epigenetic alterations as part of the abnormal transcriptional signatures linked to amyotrophic lateral sclerosis. We then applied multi-layer deep machine-learning to integrate publicly available blood and spinal cord transcriptomes and found a statistically significant correlation between their top predictor gene sets, which were significantly enriched in toll-like receptor signalling. Notably, the overrepresentation of this biological term also correlated with the transcriptional signature identified in mutant human induced pluripotent stem cell-derived motor neurons, highlighting novel insights into amyotrophic lateral sclerosis marker genes in a tissue-independent manner. Finally, using whole genome sequencing in combination with deep learning, we generated the first mutational signature for amyotrophic lateral sclerosis and defined a specific genomic profile for this disease, which is significantly correlated to ageing signatures, hinting at age as a major player in amyotrophic lateral sclerosis. This work describes innovative methodological approaches for the identification of disease signatures through the combination of multiomics analysis and provides novel knowledge on the pathological convergencies defining amyotrophic lateral sclerosis.


Asunto(s)
Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Enfermedades Neurodegenerativas , Humanos , Esclerosis Amiotrófica Lateral/metabolismo , Multiómica , Enfermedades Neurodegenerativas/metabolismo , Proteína C9orf72/genética , Superóxido Dismutasa-1/genética , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas Motoras/metabolismo
11.
Brain ; 146(9): 3760-3769, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37043475

RESUMEN

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Estados Unidos , Esclerosis Amiotrófica Lateral/genética , Predisposición Genética a la Enfermedad/genética , Proteína C9orf72/genética , Superóxido Dismutasa-1/genética
12.
N Engl J Med ; 383(2): 109-119, 2020 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-32640130

RESUMEN

BACKGROUND: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. METHODS: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. RESULTS: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose. CONCLUSIONS: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).


Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos/administración & dosificación , Superóxido Dismutasa-1/líquido cefalorraquídeo , Adulto , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/genética , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Cefalea/inducido químicamente , Humanos , Inyecciones Espinales/efectos adversos , Filamentos Intermedios , Leucocitosis/inducido químicamente , Masculino , Persona de Mediana Edad , Mutación , Oligonucleótidos/efectos adversos , Oligonucleótidos/farmacocinética , Oligonucleótidos Antisentido/efectos adversos , Oligonucleótidos Antisentido/farmacocinética , Superóxido Dismutasa-1/genética , Capacidad Vital
13.
J Neurol Neurosurg Psychiatry ; 94(8): 649-656, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-36737245

RESUMEN

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 the UNC13A gene 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 in UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as 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.


Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Enfermedades Neurodegenerativas , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/complicaciones , Demencia Frontotemporal/patología , Enfermedades Neurodegenerativas/complicaciones , Proteínas del Tejido Nervioso/genética , Polimorfismo Genético
14.
Cell Mol Life Sci ; 79(3): 189, 2022 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-35286466

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by progressive degeneration of motor neurons (MNs). Most cases are sporadic, whereas 10% are familial. The pathological mechanisms underlying the disease are partially understood, but it is increasingly being recognized that alterations in RNA metabolism and deregulation of microRNA (miRNA) expression occur in ALS. In this study, we performed miRNA expression profile analysis of iPSC-derived MNs and related exosomes from familial patients and healthy subjects. We identified dysregulation of miR-34a, miR-335 and miR-625-3p expression in both MNs and exosomes. These miRNAs regulate genes and pathways which correlate with disease pathogenesis, suggesting that studying miRNAs deregulation can contribute to deeply investigate the molecular mechanisms underlying the disease. We also assayed the expression profile of these miRNAs in the cerebrospinal fluid (CSF) of familial (fALS) and sporadic patients (sALS) and we identified a significant dysregulation of miR-34a-3p and miR-625-3p levels in ALS compared to controls. Taken together, all these findings suggest that miRNA analysis simultaneously performed in different human biological samples could represent a promising molecular tool to understand the etiopathogenesis of ALS and to develop new potential miRNA-based strategies in this new propitious therapeutic era.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Exosomas/genética , Células Madre Pluripotentes Inducidas/fisiología , MicroARNs/genética , Neuronas Motoras/fisiología , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/patología , Estudios de Casos y Controles , Comunicación Celular/genética , Células Cultivadas , Regulación de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/citología , Neuronas Motoras/patología
15.
Alzheimers Dement ; 19(4): 1245-1259, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-35993441

RESUMEN

INTRODUCTION: The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are hexanucleotide repeats in chromosome 9 open reading frame 72 (C9orf72). These repeats produce dipeptide repeat proteins with poly(PR) being the most toxic one. METHODS: We performed a kinome-wide CRISPR/Cas9 knock-out screen in human induced pluripotent stem cell (iPSC) -derived cortical neurons to identify modifiers of poly(PR) toxicity, and validated the role of candidate modifiers using in vitro, in vivo, and ex-vivo studies. RESULTS: Knock-down of NIMA-related kinase 6 (NEK6) prevented neuronal toxicity caused by poly(PR). Knock-down of nek6 also ameliorated the poly(PR)-induced axonopathy in zebrafish and NEK6 was aberrantly expressed in C9orf72 patients. Suppression of NEK6 expression and NEK6 activity inhibition rescued axonal transport defects in cortical neurons from C9orf72 patient iPSCs, at least partially by reversing p53-related DNA damage. DISCUSSION: We identified NEK6, which regulates poly(PR)-mediated p53-related DNA damage, as a novel therapeutic target for C9orf72 FTD/ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Células Madre Pluripotentes Inducidas , Animales , Humanos , Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/genética , Células Madre Pluripotentes Inducidas/metabolismo , Proteína C9orf72/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Sistemas CRISPR-Cas , Pez Cebra/genética , Pez Cebra/metabolismo , Neuronas/metabolismo , Expansión de las Repeticiones de ADN/genética , Quinasas Relacionadas con NIMA/genética , Quinasas Relacionadas con NIMA/metabolismo
16.
Ann Neurol ; 89(4): 686-697, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33389754

RESUMEN

OBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. METHODS: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. RESULTS: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). INTERPRETATION: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Dosificación de Gen , Humanos , Masculino , Reproducibilidad de los Resultados , Factores de Riesgo , Índice de Severidad de la Enfermedad , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Secuenciación Completa del Genoma
17.
Acta Neuropathol ; 144(3): 393-411, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35867112

RESUMEN

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. Although ALS is considered a motor neuron disorder, neuroinflammation also plays an important role. Recent evidence in ALS disease models indicates activation of the inflammasome and subsequent initiation of pyroptosis, an inflammatory type of cell death. In this study, we determined the expression and distribution of the inflammasome and pyroptosis effector proteins in post-mortem brain and spinal cord from ALS patients (n = 25) and controls (n = 19), as well as in symptomatic and asymptomatic TDP-43A315T transgenic and wild-type mice. Furthermore, we evaluated its correlation with the presence of TDP-43 pathological proteins and neuronal loss. Expression of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, pyroptosis effector protein cleaved Gasdermin D (GSDMD), and IL-18 was detected in microglia in human ALS motor cortex and spinal cord, indicative of canonical inflammasome-triggered pyroptosis activation. The number of cleaved GSDMD-positive precentral white matter microglia was increased compared to controls and correlated with a decreased neuronal density in human ALS motor cortex. Neither of this was observed in the spinal cord. Similar results were obtained in TDP-43A315T mice, where microglial pyroptosis activation was significantly increased in the motor cortex upon symptom onset, and correlated with neuronal loss. There was no significant correlation with the presence of TDP-43 pathological proteins both in human and mouse tissue. Our findings emphasize the importance of microglial NLRP3 inflammasome-mediated pyroptosis activation for neuronal degeneration in ALS and pave the way for new therapeutic strategies counteracting motor neuron degeneration in ALS by inhibiting microglial inflammasome/pyroptosis activation.


Asunto(s)
Esclerosis Amiotrófica Lateral , Corteza Motora , Sustancia Blanca , Esclerosis Amiotrófica Lateral/patología , Animales , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamasomas/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Microglía/patología , Corteza Motora/metabolismo , Neuronas Motoras/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis , Sustancia Blanca/patología
18.
Acta Neuropathol ; 144(3): 465-488, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35895140

RESUMEN

A 'GGGGCC' repeat expansion in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The exact mechanism resulting in these neurodegenerative diseases remains elusive, but C9 repeat RNA toxicity has been implicated as a gain-of-function mechanism. Our aim was to use a zebrafish model for C9orf72 RNA toxicity to identify modifiers of the ALS-linked phenotype. We discovered that the RNA-binding protein heterogeneous nuclear ribonucleoprotein K (HNRNPK) reverses the toxicity of both sense and antisense repeat RNA, which is dependent on its subcellular localization and RNA recognition, and not on C9orf72 repeat RNA binding. We observed HNRNPK cytoplasmic mislocalization in C9orf72 ALS patient fibroblasts, induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem motor cortex and spinal cord, in line with a disrupted HNRNPK function in C9orf72 ALS. In C9orf72 ALS/FTD patient tissue, we discovered an increased nuclear translocation, but reduced expression of ribonucleotide reductase regulatory subunit M2 (RRM2), a downstream target of HNRNPK involved in the DNA damage response. Last but not least, we showed that increasing the expression of HNRNPK or RRM2 was sufficient to mitigate DNA damage in our C9orf72 RNA toxicity zebrafish model. Overall, our study strengthens the relevance of RNA toxicity as a pathogenic mechanism in C9orf72 ALS and demonstrates its link with an aberrant DNA damage response, opening novel therapeutic avenues for C9orf72 ALS/FTD.


Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Enfermedad de Pick , Esclerosis Amiotrófica Lateral/patología , Animales , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Daño del ADN , Expansión de las Repeticiones de ADN/genética , Demencia Frontotemporal/patología , Ribonucleoproteína Heterogénea-Nuclear Grupo K/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Enfermedad de Pick/genética , ARN/metabolismo , ARN sin Sentido , Pez Cebra/genética , Pez Cebra/metabolismo
19.
J Neurol Neurosurg Psychiatry ; 93(8): 865-870, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35654584

RESUMEN

BACKGROUND: The Gold Coast criteria (GCC) have been proposed as a means of selecting patients for amyotrophic lateral sclerosis (ALS) clinical trials. We aimed to characterise disease progression according to the GCC. METHODS: Data from population-based ALS registries from the Netherlands and Belgium were analysed. The GCC additionally define ALS as lower motor neuron (LMN) dysfunction in ≥2 body regions without upper motor neuron dysfunction. Therefore, the revised El Escorial criteria (rEEC) were supplemented with a 'Gold Coast ALS' category for patients with only LMN dysfunction in ≥2 body regions. We assessed survival time, ALS Functional Rating Scale (ALSFRS-R) progression rates and between-patient variability per diagnostic category. RESULTS: We included 5957 ALS patients, of whom 600 (10.1%) fulfilled the GCC but not the rEEC, and 95 (1.6%) fulfilled only the rEEC. ALSFRS-R progression rates were similar for the rEEC (0.84 points/month) and GCC (0.81 points/month) with similar variability (standard deviation of 0.59 vs. 0.60) and median survival time (17.8 vs.18.7 months). Survival time and average progression rates varied (p<0.001) between categories. Per category, however, there was considerable between-patient variability with progression rates ranging from: -2.10 to -0.14 (definite), -1.94 to -0.06 (probable), -2.10 to -0.02 (probable laboratory supported), -1.79 to -0.02 (possible) and -1.31 to 0.08 (Gold Coast). CONCLUSIONS: The GCC broaden the definition of ALS, allowing more patients to participate in trials, while minimally impacting population heterogeneity. Given the large variability per diagnostic category, selecting only specific categories for trials may not result in a more homogeneous study population.


Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Bélgica/epidemiología , Progresión de la Enfermedad , Países Bajos
20.
Eur J Neurol ; 29(1): 345-349, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34469621

RESUMEN

BACKGROUND: Although hereditary ataxias are a group of clinically and genetically heterogeneous disorders, specific clinical clues can sometimes incriminate certain genes. This can trigger genetic testing in sporadic patients or prompt dissecting certain genes more thoroughly when initial genetic testing is negative. Also for the assembly of gene panels and interpretation of the results, genotype-phenotype correlations remain important to establish. METHODS: We clinically evaluated a Belgian family with autosomal dominant inherited sensory ataxia and variable pyramidal involvement and performed targeted clinical exome sequencing. Secondly, we retrospectively screened sequencing data of an in-house cohort of 404 patients with neuromuscular disorders for variants in the identified gene RNF170. RESULTS: All affected family members showed sensory ataxia on examination. Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings. We identified the heterozygous variant p.Arg199Cys in RNF170 in all three affected siblings of our family. We did not find additional pathogenic variants in RNF170 in our in-house neuromuscular cohort. CONCLUSIONS: We confirm the heterozygous variant p.Arg199Cys in RNF170 in a Belgian family with autosomal dominant sensory ataxia and variable pyramidal involvement. This constitutes a rare but clinically recognizable phenotype that warrants testing of RNF170. Unlike the distinctive bi-allelic loss of function variants in RNF170 associated with hereditary spastic paraplegia (HSP), the p.Arg199Cys variant is the only one reported in sensory ataxia. It is important for neurologists to be aware of this characteristic phenotype and to include this gene in gene panels for ataxia and HSP.


Asunto(s)
Ataxia , Paraplejía Espástica Hereditaria , Ataxia/genética , Humanos , Mutación/genética , Linaje , Fenotipo , Estudios Retrospectivos , Paraplejía Espástica Hereditaria/genética , Ubiquitina-Proteína Ligasas/genética
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