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Polyglucosan body myopathy type 1 (PGBM1, OMIM #615895.) is a rare autosomal recessive disorder caused by RBCK1 mutations. The patients displayed polyglucosan accumulation in skeletal and cardiac muscles, giving rise to loss of ambulation and heart failure with or without immune system dysregulation. So far, only 24 patients have been reported, all of whom exhibited symptoms before adulthood. Here, we reported the first case of an adult-onset PGBM1 patient with a novel compound heterozygous RBCK1 gene mutation consisting of a nonsense and synonymous variant affecting splicing.
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Enfermedades Musculares , Humanos , Enfermedades Musculares/genética , Mutación/genética , Codón , Fenotipo , Genotipo , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: The swift shift toward internet hospitals has relied on the willingness of medical practitioners to embrace new systems and workflows. Low engagement or acceptance by medical practitioners leads to difficulties in patient access. However, few investigations have focused on barriers and facilitators of adoption of internet hospitals from the perspective of medical practitioners. OBJECTIVE: This study aims to identify both enabling and inhibiting predictors associated with resistance and behavioral intentions of medical practitioners to use internet hospitals by combining the conservation of resources theory with the Unified Theory of Acceptance and Use of Technology and technostress framework. METHODS: A mixed methods research design was conducted to qualitatively identify the factors that enable and inhibit resistance and behavioral intention to use internet hospitals, followed by a quantitative survey-based study that empirically tested the effects of the identified factors. The qualitative phase involved conducting in-depth interviews with 16 experts in China from June to August 2022. Thematic analysis was performed using the qualitative data analysis software NVivo version 10 (QSR International). On the basis of the findings and conceptual framework gained from the qualitative interviews, a cross-sectional, anonymous, web-based survey of 593 medical practitioners in 28 provincial administrative regions of China was conducted. The data collected were analyzed using the partial least squares method, with the assistance of SPSS 27.0 (IBM Corp) and Mplus 7.0 (Muthen and Muthen), to measure and validate the proposed model. RESULTS: On the basis of qualitative results, this study identified 4 facilitators and inhibitors, namely performance expectancy, social influence, work overload, and role ambiguity. Of the 593 medical practitioners surveyed in the quantitative research, most were female (n=364, 61.4%), had a middle title (n=211, 35.6%) or primary title (n=212, 35.8%), and had an average use experience of 6 months every year. By conducting structural equation modeling, we found that performance expectancy (ß=-.55; P<.001) and work overload (ß=.16; P=.005) had the most significant impact on resistance to change. Resistance to change fully mediated the influence of performance expectancy and partially mediated the influences of social influence (variance accounted for [VAF]=43.3%; P=.002), work overload (VAF=37.2%; P=.03), and role ambiguity (VAF=12.2%; P<.001) on behavioral intentions to use internet hospitals. In addition, this study found that the sex, age, professional title, and use experience of medical practitioners significantly moderated the aforementioned influencing mechanisms. CONCLUSIONS: This study investigated the factors that facilitate or hinder medical practitioners' resistance to change and their behavioral intentions to use internet hospitals. The findings suggest that policy makers avoid the resistance and further promote the adoption of internet hospitals by ensuring performance expectancy and social influence and eliminating work overload and role ambiguity.
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Hospitales , Médicos , Humanos , Conocimientos, Actitudes y Práctica en Salud , China , Intención , Actitud del Personal de Salud , InternetRESUMEN
The huge heterogeneity of the disease progression rate may cause inconsistent findings between local activity and functional connectivity of the primary sensorimotor area (PSMA) in amyotrophic lateral sclerosis (ALS). For illustration of this hypothesis, resting-state fMRI (RS-fMRI) data were collected and analyzed on 38 "definite" or "probable" ALS patients (19 fast and 19 slow, cut off median = 0.41) and 37 matched healthy controls. Amplitude of low frequency fluctuations (ALFFs) and functional connectivity strength (FCS) were analyzed within the PSMA. There was a decreased ALFF (pFDR <.05) and FCS (p = .022) in all ALS patients. The two metrics shared about 50% of variance (R = .7) and both showed significant positive correlation with ALS Functional Rating Scale-Revised (ALSFRS-R) in the fast (p values <.034) but not in the slow progression groups. Interestingly, when regressing out the ALFF, the PSMA network FCS, especially the inter-hemisphere FCS, showed negative correlation with the ALSFRS-R score in the slow (R = -.54, p = .026) but not the fast progression group. In summary, the current results suggest that RS-fMRI local activity and network functional connectivity accounts for the severity differently in the slow and fast progression ALS patients.
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Esclerosis Amiotrófica Lateral , Corteza Sensoriomotora , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Corteza Sensoriomotora/diagnóstico por imagenRESUMEN
Nearly half of the amyotrophic lateral sclerosis (ALS) patients showed hyperintensity of the corticospinal tract (CST+), yet whether brain functional pattern differs between CST+and CST- patients remains obscure. In the current study, 19 ALS CST+, 41 ALS CST- patients and 37 healthy controls (HC) underwent resting state fMRI scans. We estimated local activity and connectivity patterns via the Amplitude of Low Frequency Fluctuations (ALFF) and the Network-Based Statistic (NBS) approaches respectively. The ALS CST+patients did not differ from the CST- patients in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) score and disease duration. ALFF of the superior frontal gyrus (SFG) and the inferior frontal gyrus pars opercularis (OIFG) were highest in the HC and lowest in the ALS CST- patients, resulting in significant group differences (PFWE<0.05). NBS analysis revealed a frontal network consisting of connections between SFG, OIFG, orbital frontal gyrus, middle cingulate cortex and the basal ganglia, which exhibited HC>ALS CST+ > ALS CST- group differences (PFWE=0.037) as well. The ALFF of the OIFG was significantly correlated with ALSFRS-R (R=0.34, P=0.028) and mean connectivity of the frontal network was trend-wise significantly correlated with disease duration (R=-0.31, P=0.052) in the ALS CST- patients. However, these correlations were insignificant in ALS CST+patients (P values > 0.8). In conclusion, The ALS CST+patients exhibited different patterns of baseline functional activity and connectivity in the frontal cortex which may indicate a functional compensatory effect.
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Structural variants (SVs) are infrequently observed in Duchenne muscular dystrophy (DMD), a condition mainly marked by deletions and point mutations in the DMD gene. SVs in DMD remain difficult to reliably detect due to the limited SV-detection capacity of conventionally used short-read sequencing technology. Herein, we present a family, a boy and his mother, with clinical signs of muscular dystrophy, elevated creatinine kinase levels, and intellectual disability. A muscle biopsy from the boy showed dystrophin deficiency. Routine molecular techniques failed to detect abnormalities in the DMD gene, however, dystrophin mRNA transcripts analysis revealed an absence of exons 59 to 79. Subsequent long-read whole-genome sequencing identified a rare complex structural variant, a 77 kb novel intragenic inversion, and a balanced translocation t(X;1)(p21.2;p13.3) rearrangement within the DMD gene, expanding the genetic spectrum of dystrophinopathy. Our findings suggested that SVs should be considered in cases where conventional molecular techniques fail to identify pathogenic variants.
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Distrofina , Distrofia Muscular de Duchenne , Translocación Genética , Distrofia Muscular de Duchenne/genética , Humanos , Masculino , Distrofina/genética , Femenino , Inversión Cromosómica/genética , Adulto , NiñoRESUMEN
BACKGROUND: The environmental effects on the prognosis of ocular myasthenia gravis (OMG) remain largely unexplored. AIM: To investigate the association between specific environmental factors and the generalization of OMG. DESIGN: The cohort study was conducted in China based on a nationwide multicenter database. METHODS: Adult patients with OMG at onset, who were followed up for at least 2 years until May 2022, were included. We collected data on demographic and clinical factors, as well as environmental factors, including latitude, socioeconomic status (per capita disposable income [PDI] at provincial level and education) and smoking. The study outcome was the time to the development of generalized myasthenia gravis (GMG). Cox models were employed to examine the association between environmental exposures and generalization. Restricted cubic spline was used to model the association of latitude with generalization risk. RESULTS: A total of 1396 participants were included. During a median follow-up of 5.15 (interquartile range [IQR] 3.37-9.03) years, 735 patients developed GMG within a median of 5.69 (IQR 1.10-15.66) years. Latitude of 20-50°N showed a U-shaped relation with generalization risk, with the lowest risk at around 30°N; both higher and lower latitudes were associated with the increased risk (P for non-linearity <0.001). Living in areas with lower PDI had 1.28-2.11 times higher risk of generalization. No significant association was observed with education or smoking. CONCLUSIONS: Latitude and provincial-level PDI were associated with the generalization of OMG in China. Further studies are warranted to validate our findings and investigate their potential applications in clinical practice and health policy.
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Miastenia Gravis , Adulto , Humanos , Estudios de Cohortes , Progresión de la Enfermedad , Miastenia Gravis/epidemiología , Miastenia Gravis/complicaciones , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVE: As a potentially life-threatening condition, myasthenia gravis (MG) has limited epidemiological studies on mortality. We aim to provide demographic distribution, geographical variation, and temporal trend of MG-related mortality in China. METHODS: The national population-based analysis was conducted based on records derived from the National Mortality Surveillance System of China. All deaths related to MG were identified from 2013 to 2020, and MG-related mortality was evaluated by sex, age, location, and year. RESULTS: A total of 4224 deaths were related to MG during 2013-2020, and the median age at death of MG was 59.45 years, significantly lower than that in the general population (75.47 years, P < 0.05). In 2020, the age-standardized mortality rate of MG was 1.86 per million people and markedly higher in males than in females (2.37 vs. 1.31 per million). The mortality rate per million was lower than 1 in young children, peaking at 2.83 only in males (vs. 0.36 in females) aged 10-19 years, and substantially increased with age, reaching the highest rate of 13.31 for males and 10.58 for females aged 80 years and older. Geographical disparity across China was observed with the highest age-standardized mortality rate in Southwest (2.53 per million). From 2013 to 2020, MG-related mortality rate showed an increasing trend with the average annual percentage change of 3.5% (95% CI, 1.4-5.6). The notable increases occurred in age 10-19 years and over 70 years. INTERPRETATION: In China, MG-related mortality was notably high among adolescent males and the elderly. The increasing death burden due to MG highlight challenges to disease management.
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Miastenia Gravis , Niño , Anciano , Masculino , Femenino , Adolescente , Humanos , Preescolar , Persona de Mediana Edad , Anciano de 80 o más Años , China/epidemiología , Manejo de la EnfermedadRESUMEN
Objective: Previous studies have reliably identified iron deposition in the motor cortex as potential pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we intended to investigate iron deposition, gray matter (GM) atrophy, and their associations with disease severity in the motor cortex and the thalamus in patients with ALS. Methods: A total of 34 patients with ALS (age 51.31 ± 8.24 years, 23 males) and 34 nonneurological controls (age 50.96 ± 9.35 years, 19 males) were enrolled between 2018 and 2020. The Revised ALS Functional Rating Scale (ALSFRS-R) and the Penn upper motor neuron (UMN) score were measured. MRI data included quantitative susceptibility mapping (QSM) for iron deposition and three-dimensional (3D) T1 for gray matter volume. After a between-group comparison, Pearson's correlation coefficient was used for identifying correlations of iron deposition, GM volume, and clinical measurements. Results: The two-sample t-tests revealed increased iron deposition in the left precentral gyrus (peak voxel T = 4.78, P SVC = 0.03) and the thalamus (peak voxel: right: T = 6.38, P SVC < 0.001; left: T = 4.64, P SVC = 0.02) in patients with ALS. GM volume of the precentral gyrus (T = -2.42, P = 0.02) and the bilateral thalamus (T = -4.10, P < 0.001) were reduced. Negative correlations were found between the increased QSM values and the decreased GM volume (P < 0.04, one-tailed) in patients with ALS. Iron deposition in the left precentral gyrus was positively correlated with the UMN score (R = 0.40, P = 0.02) and the GM volume was negatively correlated with the UMN score (R = -0.48, P = 0.004). Negative correlation between thalamic iron deposition and the ALSFRS-R (R = -0.36, P = 0.04) score was observed. Discussion: Iron deposition in the thalamus, in addition to the motor cortex, is accompanied by GM atrophy and is associated with disease severity in patients with ALS, indicating that the thalamus is also a pathological region in patients with ALS.
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Background and Purpose: Two clinical trials assessing the steroid-sparing effect of methotrexate (MTX) yielded conflicting results. Our objective was to investigate whether MTX would show a steroid-sparing effect in the treatment of generalized myasthenia gravis (MG) patients who fitted Myasthenia Gravis Foundation of America (MGFA) Class II and Class III. Methods: We performed an 18-month prospective, randomized, open-labeled trial of prednisone combined with MTX 10 mg orally every week versus prednisone alone in 40 recently diagnosed MG patients of MGFA Class II and Class III between July 2014 and July 2018. The primary endpoint was the prednisone area under the dose-time curve (AUDTC) from months 3 to 18. Secondary endpoints included changes of the Quantitative Myasthenia Gravis Score (QMG), the Myasthenia Gravis Activity of Daily Living Score (MG-ADL), initial time of prednisone reduction, the median prednisone daily dose in each month, adverse events, and treatment failures in each group. Results: Forty participants were included; among those, 5 individuals withdrew. A total of 35 participants completed 18 months of follow-up (18 in prednisone+MTX, 17 in prednisone group). Combined use of MTX reduced the month 3-18 prednisone AUDTC (prednisone+MTX 5,663.44 ± 1,678.08 mg, prednisone 6,683.94 ± 678.08 mg, p = 0.03, 95% confidence interval -1916.01 to -124.98). The initial times of prednisone reduction were 4.34 ± 1.44 months in the prednisone+MTX group and 5.56 ± 2.05 months in the prednisone group (p = 0.04, 95% CI -2.41 to -0.03). The median daily prednisone dose was significantly lower in the prednisone+MTX group at month 6 and months 9-18. No significant differences were found in QMG and MG-ADL scores between the two groups. No serious drug-related adverse events were observed in both groups. Conclusions: This study provides evidence that MTX has the steroid-sparing ability in generalized MG patients of MGFA Class II and Class III. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=10563 identifier ChiCTR-IPR-15006081.
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Metotrexato , Miastenia Gravis , Área Bajo la Curva , Humanos , Metotrexato/efectos adversos , Miastenia Gravis/tratamiento farmacológico , Prednisona/efectos adversos , Estudios ProspectivosRESUMEN
Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these mice, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. We suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Arginina/genética , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Dipéptidos/metabolismo , Femenino , Demencia Frontotemporal/patología , Glicina/genética , Masculino , Ratones , FenotipoRESUMEN
The study aims to identify clinical factors affecting tacrolimus blood trough concentration (C0) in myasthenia gravis (MG) patients and to optimize the initial dose of tacrolimus in MG treatment. A total of 103 MG patients participated in this study, and their clinical factors, medication regimens, C0 values and CYP3A5*3 polymorphisms were collected in detail. We used a linear mixed model to analyze the effect of multiple factors on the dosage-weighted C0 (C0:D) and performed subgroup analyses to investigate the consistency of correlations between influencing factors and the C0:D ratios. Among all factors, CYP3A5*3 polymorphism and age showed a strong positive correlation with C0:D ratios. The C0:D ratios (ng/ml·mg-1) were higher for CYP3A5*3/*3 than for CYP3A5*1 (mean difference: 1.038, 95% confidence interval [CI]: 0.820-1.256, P-value <0.001), and for age in the range of 45-64 and ≥ 65 years than for age < 45 years (mean difference [95% CI] and P-value: 0.531[0.257-0.805] and P-value <0.001, 0.703 [0.377-1.029] and P-value <0.001, respectively). The C0:D ratios were not related to corticosteroid dosage, body weight, sex, hematocrit or the concomitant use of calcium channel blockers. The consistencies of the correlations between C0:D ratios and CYP3A5*3 polymorphism or age were confirmed by subgroup analyses. Thus, CYP3A5*3 polymorphism and age should be considered in optimizing the initial dose of tacrolimus for MG treatment.
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Citocromo P-450 CYP3A/genética , Inmunosupresores/sangre , Miastenia Gravis/sangre , Miastenia Gravis/genética , Polimorfismo Genético/genética , Tacrolimus/sangre , Adulto , Factores de Edad , Anciano , Monitoreo de Drogas/métodos , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Miastenia Gravis/tratamiento farmacológico , Tacrolimus/uso terapéuticoRESUMEN
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, characterized by a great variety of both clinical presentations and genetic causes. Previous studies had identified two different missense mutations in SOD1 (p.R116C and p.R116G) causing familial ALS. In this study, we report a novel heterozygous missense mutation in the SOD1 gene (p.R116S) in a family with inherited ALS manifested as fast-deteriorating pure lower motor neuron symptoms. The patient displayed similar clinical picture and prognostic value to previous reported cases with different R116 substitution mutations. Modeling of all R116 substitutions in the resolved SOD1 protein structure revealed a shared mechanism with destroyed hydrogen bonds between R116 and other two residues, which might lead to protein unfolding and oligomer formation, ultimately conferring neurotoxicity.
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BACKGROUND: Intravenous immunoglobulin (IVIG) has been commonly used to treat myasthenia gravis exacerbation, but is still ineffective in nearly 30% of patients. A variable number of tandem repeat (VNTR) polymorphism in the FCGRT gene has been found to reduce the efficiency of IgG biologics. However, whether the polymorphism influences the efficacy of IVIG in generalized myasthenia gravis (MG) patients with exacerbations remains unknown. METHODS: The distribution of VNTR genotypes was analyzed in 334 patients with MG. Varied VNTR alleles were determined by capillary electrophoresis and confirmed by Sanger sequencing. Information of endogenous IgG levels were collected in patients without previous immunotherapy (n = 26). Medical records of patients who received IVIG therapy were retrospectively analyzed for therapeutic outcomes of IVIG treatment (n = 61). Patients whose Activities of Daily Living scores decreased by 2 or more points on day 14 were considered responders to the treatment. RESULTS: The VNTR3/3 and VNTR2/3 genotypes were detected in 96.7% (323/334) and 3.4% (11/334) patients, respectively. Patients with VNTR2/3 heterozygosity had lower endogenous IgG levels than those with VNTR3/3 homozygosity (9.81 ± 2.61 g/L versus 12.41 ± 2.45g/L, p = 0.016). The response rate of IVIG therapy was 78.7% (48/61). All responders and nine non-responders were VNTR3/3 homozygotes, whereas all the patients with VNTR2/3 genotypes were non-responders (n = 4). In patients who took IVIG treatments, endogenous IgG levels were significantly lower in non-responders compared with responders (12.93 ± 2.24 g/L versus 8.85 ± 2.69 g/L, p = 0.006), especially in VNTR2/3 heterozygotes (7.86 ± 1.78 g/L, p = 0.001). CONCLUSION: The VNTR2/3 genotype could influence endogenous IgG levels and serve as a predictive marker for poor responses to IVIG in MG patients.
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The most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an intronic hexanucleotide repeat expansion in the C9orf72 gene. In disease, RNA transcripts containing this expanded region undergo repeat-associated non-AUG translation to produce dipeptide repeat proteins (DPRs), which are detected in brain and spinal cord of patients and are neurotoxic both in vitro and in vivo paradigms. We reveal here a novel pathogenic mechanism for the most abundantly detected DPR in ALS/FTD autopsy tissues, poly-glycine-alanine (GA). Previously, we showed motor dysfunction in a GA mouse model without loss of motor neurons. Here, we demonstrate that mobile GA aggregates are present within neurites, evoke a reduction in synaptic vesicle-associated protein 2 (SV2), and alter Ca2+ influx and synaptic vesicle release. These phenotypes could be corrected by restoring SV2 levels. In GA mice, loss of SV2 was observed without reduction of motor neuron number. Notably, reduction in SV2 was seen in cortical and motor neurons derived from patient induced pluripotent stem cell lines, suggesting synaptic alterations also occur in patients.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Alanina , Esclerosis Amiotrófica Lateral/genética , Animales , Proteína C9orf72/genética , Dipéptidos , Demencia Frontotemporal/genética , Glicina , Humanos , Ratones , Neuronas MotorasRESUMEN
Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat-associated non-AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated-PERK and the phosphorylated-eif2α complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases.
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Esclerosis Amiotrófica Lateral/patología , Proteína C9orf72/genética , Dipéptidos/biosíntesis , Demencia Frontotemporal/patología , Neuronas/patología , Biosíntesis de Proteínas , Secuencias Repetitivas de Ácidos Nucleicos , Células Cultivadas , HumanosRESUMEN
An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.
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Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Demencia Frontotemporal/genética , Degeneración Nerviosa/genética , Proteínas de Unión al GTP rab5/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Expansión de las Repeticiones de ADN/genética , Modelos Animales de Enfermedad , Endosomas/genética , Demencia Frontotemporal/patología , Regulación de la Expresión Génica/genética , Haploinsuficiencia/genética , Humanos , Intrones/genética , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Mutación , Degeneración Nerviosa/fisiopatologíaRESUMEN
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two apparently distinct neurodegenerative diseases, the former characterized by selective loss of motor neurons in the brain and spinal cord and the latter characterized by selective atrophy of frontal and temporal lobes. Over the years, however, growing evidence from clinical, pathological and genetic findings has suggested that ALS and FTD belong to the same clinic-pathological spectrum disorder. This concept has been further supported by the identification of the most common genetic cause for both diseases, an aberrantly expanded hexanucleotide repeat GGGGCC/ CCCCGG sequence located in a non-coding region of the gene C9orf72. Three hypotheses have been proposed to explain how this repeats expansion causes diseases: 1) C9orf72 haploinsufficiency-expanded repeats interfere with transcription or translation of the gene, leading to decreased expression of the C9orf72 protein; 2) RNA gain of function-RNA foci formed by sense and antisense transcripts of expanded repeats interact and sequester essential RNA binding proteins, causing neurotoxicity; 3) Repeat associated non-ATG initiated (RAN) translation of expanded sense GGGGCC and antisense CCCCGG repeats produces potential toxic dipeptide repeat protein (DPR). In this review, we assess current evidence supporting or arguing against each proposed mechanism in C9 ALS/FTD disease pathogenesis. Additionally, controversial findings are also discussed. Lastly, we discuss the possibility that the three pathogenic mechanisms are not mutually exclusive and all three might be involved in disease.
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Esclerosis Amiotrófica Lateral/metabolismo , Expansión de las Repeticiones de ADN , Demencia Frontotemporal/metabolismo , Proteínas/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Proteína C9orf72 , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Haploinsuficiencia , Humanos , Mutación , Biosíntesis de Proteínas , Proteínas/metabolismoRESUMEN
Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these expansions undergo repeat-associated non-ATG translation (RAN-T) to form five dipeptide repeat proteins (DPRs). DPRs are found as aggregates throughout the CNS of C9orf72-ALS/FTD patients, and some cause degeneration when expressed in vitro in neuronal cultures and in vivo in animal models. The spread of characteristic disease-related proteins drives the progression of pathology in many neurodegenerative diseases. While DPR toxic mechanisms continue to be investigated, the potential for DPRs to spread has yet to be determined. Using different experimental cell culture platforms, including spinal motor neurons derived from induced pluripotent stem cells from C9orf72-ALS patients, we found evidence for cell-to-cell spreading of DPRs via exosome-dependent and exosome-independent pathways, which may be relevant to disease.
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Esclerosis Amiotrófica Lateral/metabolismo , Proteína C9orf72/metabolismo , Dipéptidos/química , Demencia Frontotemporal/metabolismo , Secuencias Repetitivas de Aminoácido , Animales , Dipéptidos/metabolismo , Exosomas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas Motoras/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Ratas , Médula Espinal/patologíaRESUMEN
Expanded GGGGCC (G4C2) nucleotide repeats within the C9ORF72 gene are the most common genetic mutation associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sense and antisense transcripts of these expansions are translated to form five dipeptide repeat proteins (DRPs). We employed primary cortical and motor neuron cultures, live-cell imaging, and transgenic fly models and found that the arginine-rich dipeptides, in particular Proline-Arginine (PR), are potently neurotoxic. Factors that anticipated their neurotoxicity included aggregation in nucleoli, decreased number of processing bodies, and stress granule formation, implying global translational dysregulation as path accountable for toxicity. Nuclear PR aggregates were also found in human induced motor neurons and postmortem spinal cord tissues from C9ORF72 ALS and ALS/FTD patients. Intronic G4C2 transcripts, but not loss of C9ORF72 protein, are also toxic to motor and cortical neurons. Interestingly, G4C2 transcript-mediated neurotoxicity synergizes with that of PR aggregates, suggesting convergence of mechanisms.