Diagnostic C9orf72 hexanucleotide repeat expansions(C9-HRE)is essential for the early and accurate diagnosis of amyotrophic lateral sclerosis(ALS)and will provide support for the prognosis and gene therapy of ALS.In t...Diagnostic C9orf72 hexanucleotide repeat expansions(C9-HRE)is essential for the early and accurate diagnosis of amyotrophic lateral sclerosis(ALS)and will provide support for the prognosis and gene therapy of ALS.In the present study,by combining catalytic hairpin assembly(CHA)with Mycobacterium smegmatis porin A(MspA)nanopore,a new nanopore-based strategy for the detection of C9-HRE was reported.Less than 30 repeats of C9-HRE could be detected via this method,and the results have the potential to help distinguish between patients and healthy individuals.Moreover,the method demonstrated its great specificity for C9-HRE by identifying other repeat expansions.Given the high selectivity,this approach had been successfully used to detect C9-HRE in cell and blood samples with high accuracy.This detection strategy is user-friendly and has a strong anti-interference ability,thus providing a powerful tool for clinical diagnosis.展开更多
GGGGCC repeat expansions in the C9 ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia(c9 ALS/FTD). It has been reported that hexanucleotide repeat expansions in C9 ORF72 ...GGGGCC repeat expansions in the C9 ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia(c9 ALS/FTD). It has been reported that hexanucleotide repeat expansions in C9 ORF72 produce five dipeptide repeat(DPR) proteins by an unconventional repeat-associated non-ATG(RAN)translation. Within the five DPR proteins, poly-PR and poly-GR that contain arginine are more toxic than the other DPRs(poly-GA, poly-GP, and poly-PA). Here, we demonstrated that poly-PR peptides transferred into cells by endocytosis in a clathrin-dependent manner, leading to endoplasmic reticulum stress and cell death. In SH-SY5 Y cells and primary cortical neurons, poly-PR activated JUN amino-terminal kinase(JNK) and increased the levels of p53 and Bax. The uptake of poly-PR peptides by cells was significantly inhibited by knockdown of clathrin or by chlorpromazine, an inhibitor that blocks clathrin-mediated endocytosis. Inhibition of clathrin-dependent endocytosis by chlorpromazine significantly blocked the transfer of poly-PR peptides into cells, and attenuated poly-PRinduced JNK activation and cell death. Our data revealed that the uptake of poly-PR undergoes clathrin-dependentendocytosis and blockade of this process prevents the toxic effects of synthetic poly-PR peptides.展开更多
Background:The GGGGCC(G4C2)repeat expansion in the human open reading frame 72 on chromosome 9,C9orf72,is the most common cause of amyotrophic lateral sclerosis(ALS).Studies in transgenic mouse models have linked the ...Background:The GGGGCC(G4C2)repeat expansion in the human open reading frame 72 on chromosome 9,C9orf72,is the most common cause of amyotrophic lateral sclerosis(ALS).Studies in transgenic mouse models have linked the pathogenic mechanism of G4C2 repeat expansion to RNA foci or the accumulation of unnatural dipeptide repeats in neurons.However,only one of the existing transgenic mouse lines developed typical ALS.Methods:C9orf72 knockin rats were generated by knockin of 80 G4C2 repeats with human flanking fragments within exon1a and exon1b at the rat C9orf72 locus.Protein expression was detected by western blot.Motor coordination and grip force were measured using a Rotarod test and a grip strength test.Neurodegeneration was assessed by Nissl staining with cresyl violet.Results:C9orf72 haploinsufficiency reduced C9orf72 protein expression 40%in the cerebrum,cerebellum and spinal cords from knockin rats(P<.05).The knockin(KI)rats developed motor deficits from 4 months of age.Their falling latencies and grip force were decreased by 67%(P<.01)and 44%(P<.01),respectively,at 12 months of age compared to wild-type(WT)mice.The knockin of the hexanucleotide repeat expansion(HRE)caused a 47%loss of motor neurons in the spinal cord(P<.001)and 25%(5/20)of female KI rats developed hind limb paralysis at 13 to 24 months.Conclusion:Motor defects in KI rats may result from neurotoxicity caused by HRE and the resulting reduction in C9orf72 protein due to haploinsufficiency.These KI rats could be a useful model for investigating the contributions of loss-of-function to neurotoxicity in C9orf72-related ALS.展开更多
Since the discovery of the C9ORF72 gene in2011,great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms;it is the most common genetic cause of amyotro...Since the discovery of the C9ORF72 gene in2011,great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms;it is the most common genetic cause of amyotrophic lateral sclerosis(ALS) and frontotemporal dementia(FTD).ALS patients with C9ORF72 expansion show heterogeneous symptoms.Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients.Pathological and clinical features of C9ORF72 patients have been well mimicked via several models,including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins.The mechanisms implicated in C9ORF72 pathology include DNA damage,changes of RNA metabolism,alteration of phase separation,and impairment of nucleocytoplasmic transport,which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into nonC9ORF72 expansion-related ALS,FTD,and other neurodegenerative diseases.展开更多
Many diseases are caused by the expansion of simple sequence repeats scattered throughout the human genome;they are defined as repeat expansion diseases.The size of the repeat unit ranges from trinucleotides(the vast ...Many diseases are caused by the expansion of simple sequence repeats scattered throughout the human genome;they are defined as repeat expansion diseases.The size of the repeat unit ranges from trinucleotides(the vast majority)to tetranucleotides,pentanucleotides,hexan cleotides,and even dodecanucleotides[1].Expansions of the hexanucleotide GGGGCC in the C9orf72 gene are the most frequent genetic cause of amyotrophic lateral sclero・sis(ALS)and frontotemporal dementia(FTD)[2].In addition to ALS and FTD,C9orf72 repeat expansions may also be associated with Alzheimer's disease(AD),since the rate of such expansions in AD cases(0.57%)is higher than normal(0.11%)[3].However,the exact role of C9orf72 in AD is still unclear.展开更多
The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding pla...The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.展开更多
Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GG...Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and FTD.According to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)proteins.Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains unclear.In the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced autophagy.Moreover,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells.Importantly,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.展开更多
Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to r...Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.展开更多
Amyotrophic lateral sclerosis（ALS）is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,includin...Amyotrophic lateral sclerosis（ALS）is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis.Indeed,while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants,it is now well established that mitochondria become also dysfunctional in other ALS conditions.In such context,the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death,by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy.Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system.This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.展开更多
基金supported by a grant from the National Key Research and Development Program of China(No.2022YFB3205600)National Natural Science Foundation of China(No.82004341)+3 种基金China Postdoctoral Science Foundation(No.2022M712286)Sichuan Science and Technology Program(No.2020JDTD0022)Sichuan Administration of Traditional Chinese Medicine(No.2023MS078)Sichuan University Postdoctoral Interdisciplinary Innovation Fund(No.JCXK2225)。
文摘Diagnostic C9orf72 hexanucleotide repeat expansions(C9-HRE)is essential for the early and accurate diagnosis of amyotrophic lateral sclerosis(ALS)and will provide support for the prognosis and gene therapy of ALS.In the present study,by combining catalytic hairpin assembly(CHA)with Mycobacterium smegmatis porin A(MspA)nanopore,a new nanopore-based strategy for the detection of C9-HRE was reported.Less than 30 repeats of C9-HRE could be detected via this method,and the results have the potential to help distinguish between patients and healthy individuals.Moreover,the method demonstrated its great specificity for C9-HRE by identifying other repeat expansions.Given the high selectivity,this approach had been successfully used to detect C9-HRE in cell and blood samples with high accuracy.This detection strategy is user-friendly and has a strong anti-interference ability,thus providing a powerful tool for clinical diagnosis.
基金supported by the National Natural Science Foundation of China (81761148024 and 31871023)the National Key Scientific R&D Program of China (2016YFC1306000)+1 种基金Suzhou Clinical Research Center of Neurological Disease (Szzx201503)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, China
文摘GGGGCC repeat expansions in the C9 ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia(c9 ALS/FTD). It has been reported that hexanucleotide repeat expansions in C9 ORF72 produce five dipeptide repeat(DPR) proteins by an unconventional repeat-associated non-ATG(RAN)translation. Within the five DPR proteins, poly-PR and poly-GR that contain arginine are more toxic than the other DPRs(poly-GA, poly-GP, and poly-PA). Here, we demonstrated that poly-PR peptides transferred into cells by endocytosis in a clathrin-dependent manner, leading to endoplasmic reticulum stress and cell death. In SH-SY5 Y cells and primary cortical neurons, poly-PR activated JUN amino-terminal kinase(JNK) and increased the levels of p53 and Bax. The uptake of poly-PR peptides by cells was significantly inhibited by knockdown of clathrin or by chlorpromazine, an inhibitor that blocks clathrin-mediated endocytosis. Inhibition of clathrin-dependent endocytosis by chlorpromazine significantly blocked the transfer of poly-PR peptides into cells, and attenuated poly-PRinduced JNK activation and cell death. Our data revealed that the uptake of poly-PR undergoes clathrin-dependentendocytosis and blockade of this process prevents the toxic effects of synthetic poly-PR peptides.
基金National Natural Science Foundation of China(81571222),CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-1-004)Beijing Municipal Natural Science Foundation(7172135)。
文摘Background:The GGGGCC(G4C2)repeat expansion in the human open reading frame 72 on chromosome 9,C9orf72,is the most common cause of amyotrophic lateral sclerosis(ALS).Studies in transgenic mouse models have linked the pathogenic mechanism of G4C2 repeat expansion to RNA foci or the accumulation of unnatural dipeptide repeats in neurons.However,only one of the existing transgenic mouse lines developed typical ALS.Methods:C9orf72 knockin rats were generated by knockin of 80 G4C2 repeats with human flanking fragments within exon1a and exon1b at the rat C9orf72 locus.Protein expression was detected by western blot.Motor coordination and grip force were measured using a Rotarod test and a grip strength test.Neurodegeneration was assessed by Nissl staining with cresyl violet.Results:C9orf72 haploinsufficiency reduced C9orf72 protein expression 40%in the cerebrum,cerebellum and spinal cords from knockin rats(P<.05).The knockin(KI)rats developed motor deficits from 4 months of age.Their falling latencies and grip force were decreased by 67%(P<.01)and 44%(P<.01),respectively,at 12 months of age compared to wild-type(WT)mice.The knockin of the hexanucleotide repeat expansion(HRE)caused a 47%loss of motor neurons in the spinal cord(P<.001)and 25%(5/20)of female KI rats developed hind limb paralysis at 13 to 24 months.Conclusion:Motor defects in KI rats may result from neurotoxicity caused by HRE and the resulting reduction in C9orf72 protein due to haploinsufficiency.These KI rats could be a useful model for investigating the contributions of loss-of-function to neurotoxicity in C9orf72-related ALS.
基金supported by the National Natural Science Foundation of China (31871023 and 31970966)the National Key Scientific R&D Program of China (2016YFC1306000)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘Since the discovery of the C9ORF72 gene in2011,great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms;it is the most common genetic cause of amyotrophic lateral sclerosis(ALS) and frontotemporal dementia(FTD).ALS patients with C9ORF72 expansion show heterogeneous symptoms.Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients.Pathological and clinical features of C9ORF72 patients have been well mimicked via several models,including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins.The mechanisms implicated in C9ORF72 pathology include DNA damage,changes of RNA metabolism,alteration of phase separation,and impairment of nucleocytoplasmic transport,which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into nonC9ORF72 expansion-related ALS,FTD,and other neurodegenerative diseases.
基金the National Natural Science Foundation of China(92049104 and 82103210)the Research Start-up Project by Hangzhou Normal University(4125C5021920453 and 4125C50220204106).
文摘Many diseases are caused by the expansion of simple sequence repeats scattered throughout the human genome;they are defined as repeat expansion diseases.The size of the repeat unit ranges from trinucleotides(the vast majority)to tetranucleotides,pentanucleotides,hexan cleotides,and even dodecanucleotides[1].Expansions of the hexanucleotide GGGGCC in the C9orf72 gene are the most frequent genetic cause of amyotrophic lateral sclero・sis(ALS)and frontotemporal dementia(FTD)[2].In addition to ALS and FTD,C9orf72 repeat expansions may also be associated with Alzheimer's disease(AD),since the rate of such expansions in AD cases(0.57%)is higher than normal(0.11%)[3].However,the exact role of C9orf72 in AD is still unclear.
文摘The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.
基金This work was supported by the National Natural Science Foundation of China(Nos.82022022,32371018 and 82071274)a Project Funded by Jiangsu Key Laboratory of Neuropsychiatric Diseases(BM2013003,China)+4 种基金a Key Project of Natural Science Foundation of Jiangsu Provincial Higher Education Institutions(23KJA310005,China)a Project Funded by the Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University(MP13202823,China)a Project Funded by the Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and a Project Funded by the Priority Academic Program Development of the Jiangsu Higher Education Institutes(PAPD).J.H.M.P.was supported Science Foundation Ireland(17/COEN/3474,17/JPND/3455)Q.M.is a recipient of an RCSI International StAR Ph.D.scholarship.N.L.was supported by the Postgraduate Research&Practice Innovation Program of Jiangsu Province.K.Y.T.,was supported by the financial support from the Science and Technology Development Fund,Macao SAR(File no.0062/2021/A,China)University of Macao(File no.MYRG2022-00171-FHS,China).
文摘Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and FTD.According to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)proteins.Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains unclear.In the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced autophagy.Moreover,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells.Importantly,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.
基金supported by a grant from the Association Française contre les Myopathies(AFM Téléthongrant 23667,to JCL).
文摘Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.
文摘Amyotrophic lateral sclerosis（ALS）is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis.Indeed,while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants,it is now well established that mitochondria become also dysfunctional in other ALS conditions.In such context,the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death,by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy.Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system.This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.
