scholarly journals Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 15 ◽  
pp. 263310552095730 ◽  
Author(s):  
Mara-Luciana Floare ◽  
Scott P. Allen
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Chromosome 9 ◽  
Metabolic Dysfunction ◽  
Superoxide Dismutase 1 ◽  
Gene Encoding ◽  
Reading Frame ◽  
Fused In Sarcoma ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder for which there is no effective curative treatment available and minimal palliative care. Mutations in the gene encoding the TAR DNA-binding protein 43 (TDP-43) are a well-recognized genetic cause of ALS, and an imbalance in energy homeostasis correlates closely to disease susceptibility and progression. Considering previous research supporting a plethora of downstream cellular impairments originating in the histopathological signature of TDP-43, and the solid evidence around metabolic dysfunction in ALS, a causal association between TDP-43 pathology and metabolic dysfunction cannot be ruled out. Here we discuss how TDP-43 contributes on a molecular level to these impairments in energy homeostasis, and whether the protein’s pathological effects on cellular metabolism differ from those of other genetic risk factors associated with ALS such as superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72) and fused in sarcoma (FUS).

scholarly journals The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

2018 ◽  
Vol 19 (10) ◽  
pp. 3137 ◽  
Author(s):  
Anna Konopka ◽  
Julie Atkin
Keyword(s):  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Repeat Expansion ◽  
Chromosome 9 ◽  
Gene Encoding ◽  
C9orf72 Repeat Expansion ◽  
Reading Frame ◽  
Early Onset Dementia ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.

scholarly journals Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

2021 ◽  
Vol 22 (2) ◽  
pp. 904
Author(s):  
Sophie Layalle ◽  
Laetitia They ◽  
Sarah Ourghani ◽  
Cédric Raoul ◽  
Laurent Soustelle
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Drosophila Melanogaster ◽  
Fruit Fly ◽  
Chromosome 9 ◽  
Cellular Mechanisms ◽  
Reading Frame ◽  
Fused In Sarcoma ◽  
Drosophila Research ◽  
Inherited Mutations ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motoneurons. Most ALS cases are sporadic but approximately 10% of ALS cases are due to inherited mutations in identified genes. ALS-causing mutations were identified in over 30 genes with superoxide dismutase-1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), fused in sarcoma (FUS), and TAR DNA-binding protein (TARDBP, encoding TDP-43) being the most frequent. In the last few decades, Drosophila melanogaster emerged as a versatile model for studying neurodegenerative diseases, including ALS. In this review, we describe the different Drosophila ALS models that have been successfully used to decipher the cellular and molecular pathways associated with SOD1, C9orf72, FUS, and TDP-43. The study of the known fruit fly orthologs of these ALS-related genes yielded significant insights into cellular mechanisms and physiological functions. Moreover, genetic screening in tissue-specific gain-of-function mutants that mimic ALS-associated phenotypes identified disease-modifying genes. Here, we propose a comprehensive review on the Drosophila research focused on four ALS-linked genes that has revealed novel pathogenic mechanisms and identified potential therapeutic targets for future therapy.

scholarly journals Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jacqueline Dominguez ◽  
Jeryl Tan Yu ◽  
Yi Jayne Tan ◽  
Arlene Ng ◽  
Ma Fe De Guzman ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Positive Family History ◽  
Clinical Manifestations ◽  
The Philippines ◽  
Chromosome 9 ◽  
Genetic Modifiers ◽  
Reading Frame ◽  
Hexanucleotide Repeat ◽  
Lateral Sclerosis

Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.

scholarly journals Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

2020 ◽  
Vol 21 (10) ◽  
pp. 3647 ◽  
Author(s):  
Francesca Trojsi ◽  
Giulia D’Alvano ◽  
Simona Bonavita ◽  
Gioacchino Tedeschi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Risk ◽  
Genetic Mutation ◽  
Chromosome 9 ◽  
Patient Specific ◽  
Reading Frame ◽  
Hexanucleotide Repeat ◽  
Sporadic Als ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

scholarly journals Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

2020 ◽  
pp. jnnp-2020-324647
Author(s):  
Virgilio Kmetzsch ◽  
Vincent Anquetil ◽  
Dario Saracino ◽  
Daisy Rinaldi ◽  
Agnès Camuzat ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Chromosome 9 ◽  
Differentially Expressed ◽  
Reading Frame ◽  
Expression Levels ◽  
Clinical Onset ◽  
Plasma Microrna ◽  
A Prospective Study ◽  
Lateral Sclerosis

ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.

scholarly journals Glucose clearance and uptake is increased in the SOD1G93A mouse model of amyotrophic lateral sclerosis through an insulin-independent mechanism

2020 ◽  
Author(s):  
Tanya S. McDonald ◽  
Vinod Kumar ◽  
Jenny N. Fung ◽  
Trent M. Woodruff ◽  
John D. Lee
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Disease Stage ◽  
Metabolic Disturbances ◽  
Symptomatic Disease ◽  
Lateral Sclerosis

AbstractMetabolic disturbances are associated with the progression of the neurodegenerative disorder, amyotrophic lateral sclerosis (ALS), however the molecular events that drive energy imbalances in ALS are not completely understood. In this study we aimed to elucidate deficits in energy homeostasis in the SOD1G93A mouse model of ALS. We identified that SOD1G93A mice at mid-symptomatic disease stage have increased oxygen consumption and faster exogenous glucose uptake, despite presenting with normal insulin tolerance. Fasting glucose homeostasis was also disturbed, along with increased liver glycogen stores, despite elevated circulating glucagon, suggesting that glucagon signalling is impaired. Metabolic gene expression profiling of livers indicated that glucose cannot be utilised efficiently in SOD1G93A mice. Overall, we demonstrate that glucose homeostasis and uptake are altered in SOD1G93A mice, which is linked to an increase in insulin-independent glucose uptake and a disturbance in glucagon sensitivity, suggesting glucagon secretion and signalling could be potential therapeutic targets for ALS.

scholarly journals ALS-Related Mutant SOD1 Aggregates Interfere with Mitophagy by Sequestering the Autophagy Receptor Optineurin

2020 ◽  
Vol 21 (20) ◽  
pp. 7525
Author(s):  
Yeong Jin Tak ◽  
Ju-Hwang Park ◽  
Hyangshuk Rhim ◽  
Seongman Kang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cellular Cytotoxicity ◽  
Superoxide Dismutase 1 ◽  
Gene Encoding ◽  
Abnormal Protein ◽  
Mutant Sod1 ◽  
Familial Als ◽  
The Relationship ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive demise of motor neurons. One of the causes of familial ALS is the mutation of the gene encoding superoxide dismutase 1 (SOD1), which leads to abnormal protein aggregates. How SOD1 aggregation drives ALS is still poorly understood. Recently, ALS pathogenesis has been functionally implicated in mitophagy, specifically the clearance of damaged mitochondria. Here, to understand this mechanism, we investigated the relationship between the mitophagy receptor optineurin and SOD1 aggregates. We found that mutant SOD1 (mSOD1) proteins associate with and then sequester optineurin, which is required to form the mitophagosomes, to aggregates in N2a cells. Optineurin recruitment into mSOD1 aggregates resulted in a reduced mitophagy flux. Furthermore, we observed that an exogenous augmentation of optineurin alleviated the cellular cytotoxicity induced by mSOD1. Taken together, these studies demonstrate that ALS-linked mutations in SOD1 interfere with the mitophagy process through optineurin sequestration, suggesting that the accumulation of damaged mitochondria may play a crucial role in the pathophysiological mechanisms contributing to ALS.

scholarly journals Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 84
Author(s):  
Alma Osmanovic ◽  
Isabel Gogol ◽  
Helge Martens ◽  
Maylin Widjaja ◽  
Kathrin Müller ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disorder ◽  
Muscular Atrophy ◽  
Gene Encoding ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Sporadic Cases ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in neurodegeneration. Thus, variants in the DHTKD1 gene encoding dehydrogenase E1 and transketolase domain containing 1 previously linked to 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth (CMT) disease type 2, and spinal muscular atrophy (SMA) were identified. In two independent European ALS cohorts (n = 643 cases), 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants predicted to be deleterious. Four DHTKD1 variants were previously described pathogenic variants, seven were recurrent, and eight were located in the E1_dh dehydrogenase domain. Nonsense variants located in the E1_dh domain were significantly more prevalent in ALS patients versus controls. The phenotype of ALS patients carrying DHTKD1 variants partially overlapped with CMT and SMA by presence of sensory impairment and a higher frequency of LMN-predominant cases. Our results argue towards rare heterozygous DHTKD1 variants as potential contributors to ALS phenotype and, possibly, pathogenesis.

Autoimmunity and Frontotemporal Dementia

2018 ◽  
Vol 15 (7) ◽  
pp. 602-609 ◽  
Author(s):  
Antonella Alberici ◽  
Viviana Cristillo ◽  
Stefano Gazzina ◽  
Alberto Benussi ◽  
Alessandro Padovani ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Language Impairment ◽  
Neurodegenerative Disorder ◽  
Chromosome 9 ◽  
Bibliographic Databases ◽  
Extensive Literature ◽  
Genetic Studies ◽  
Reading Frame ◽  
Current State ◽  
Extensive Evaluation

Background: Frontotemporal Dementia (FTD) is a neurodegenerative disorder which asymmetrically affects the frontotemporal lobe, characterized by behavioural abnormalities, language impairment, and deficits of executive functions. Genetic studies identified mutations causing the disease, namely Microtubule Associated Protein Tau (MAPT), Granulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) mutations, which contributed to elucidate the molecular pathways involved in brain depositions of either Tau or TAR DNA-binding protein 43 (TDP43) inclusions. However, in the majority of sporadic FTD patients, the mechanisms triggering Tau or TDP43 protein deposition are still to be uncovered. Objective: We aimed to present an extensive evaluation of literature data on immune homeostasis in FTD, in order to provide potentially evidence-based approaches for a disease still orphan of any treatment. Methods: A structured search of bibliographic databases from peer-reviewed literature was pursued focusing on autoimmunity in the brain and FTD. Results: One-hundred-fourteen papers were included in this review. The majority of studies (32) were represented by extensive literature revision on immunity, central nervous system (CNS) and autoimmunity; neuroimaging papers (11) in autoimmune diseases were evaluated, and immunomodulatory approaches (25) were revised. Six papers were found specifically related to FTD and autoimmune hypothesis, the other papers referring to current state of art on FTD. Conclusion: Overall this review contribute to expand the knowledge of a possible immune hypothesis in FTD, suggesting therapeutic perspectives in autoimmune related neurodegeneration, to reduce or revert the disease.

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