Mechanisms Of Amyotrophic Lateral Sclerosis Research Articles

Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS.

The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS.

Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilised to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation (IE), and stimulus response (SR) curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior (PA), lateral-medial (LM), and anterior-posterior (AP) direction. Mean SICI, between interstimulus interval (ISI) of 1-to-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in PA (P = 0.044) and LM (P = 0.005) but not the AP (P = 0.08) directions. A significant correlation between mean SICI oriented in a PA direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between ISI 1-to-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in PA (P = 0.035) and LM (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the AP direction was comparable between ALS and controls (P = 0.482). The IE was significantly increased in ALS patients when recorded with the TMS coil oriented in PA (P = 0.041) and LM (P = 0.003) directions. In ALS patients, a significant increase in the SR curve gradient was evident compared to controls when recorded with TMS coil oriented in PA (P < 0.001), LM (P < 0.001) and AP (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

Data-independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis.

While unbiased proteomics of human cerebrospinal fluid (CSF) has been used successfully to identify biomarkers of amyotrophic lateral sclerosis (ALS), high-abundance proteins mask the presence of lower abundance proteins that may have diagnostic and prognostic value. However, developments in mass spectrometry (MS) proteomic data acquisition methods offer improved protein depth. In this study, MS with library-free data-independent acquisition (DIA) was used to compare the CSF proteome of people with ALS (n = 40), healthy (n = 15) and disease (n = 8) controls. Quantified protein groups were subsequently correlated with clinical variables. Univariate analysis identified 7 proteins, all significantly upregulated in ALS versus healthy controls, and 9 with altered abundance in ALS versus disease controls (FDR < 0.1). Elevated chitotriosidase-1 (CHIT1) was common to both comparisons and was proportional to ALS disability progression rate (Pearson r = 0.41, FDR-adjusted p = 0.035) but not overall survival. Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1; upregulated in ALS versus healthy controls) was proportional to disability progression rate (Pearson r = 0.53, FDR-adjusted p = 0.003) and survival (Kaplan Meier log-rank p = 0.013) but not independently in multivariate proportional hazards models. Weighted correlation network analysis was used to identify functionally relevant modules of proteins. One module, enriched for inflammatory functions, was associated with age at symptom onset (Pearson r = 0.58, FDR-adjusted p = 0.005) and survival (Hazard Ratio = 1.78, FDR = 0.065), and a second module, enriched for endoplasmic reticulum proteins, was negatively correlated with disability progression rate (r = -0.42, FDR-adjusted p = 0.109). DIA acquisition methodology therefore strengthened the biomarker candidacy of CHIT1 and UCHL1 in ALS, while additionally highlighted inflammatory and endoplasmic reticulum proteins as novel sources of prognostic biomarkers.

GM1 ganglioside exerts protective effects against glutamate-excitotoxicity via its oligosaccharide in wild-type and amyotrophic lateral sclerosis motor neurons.

Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid-containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1-OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: Itsadministration to WT and SOD1G93A motor neurons affected by glutamate-induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment. Importantly, the GM1-OS faithfully replicates GM1 activity, emphasizing that even in ALS the protective function of GM1 strictly depends on its pentasaccharide.

Pathological mechanisms of amyotrophic lateral Sclerosis.

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. Thus, the journey to understanding or treating amyotrophic lateral sclerosis is still a long one. According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis. In addition, we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis. Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

The role of peripheral immunity in ALS: a population-based study.

Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population-based ALS cohort using readily available hematological indexes. We collected clinical data and the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d'Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic-immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. Neutrophils (P = 0.001) and markers of increased innate immunity (NLR, P = 0.008 and SII, P = 0.006) were associated with a faster disease progression. Similarly, elevated innate immunity correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415). The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.

Front Cover Image, Volume 43, Issue 4

The cover image is based on the Review Article Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno-associated viral vectors by Jessica Merjane et al., https://doi.org/10.1002/med.21937.

288 Harnessing the potential of transcriptional adaptation as a mechanism for Amyotrophic lateral sclerosis

OBJECTIVES/GOALS: Understanding the mechanism of transcriptional adaptation may contribute to an explanation for variation in clinical manifestations of Amyotrophic lateral sclerosis patient phenotypes. METHODS/STUDY POPULATION: To examine transcriptional adaptation, we utilized gene editing tools in HT1080 cells and patient samples with known CHCHD10 mutations causative for Amyotrophic lateral sclerosis. Frameshift mutations were performed via CRISPR-Cas9. Ribonucleoprotein electroporation was used to transfect cells and DNA sequencing was conducted to validate gene editing. To validate transcriptional adaption, changes in levels of protein and gene expression will be measured via immunoblot and quantification of CHCHD10 and CHCHCD2 from whole cells lysates of the edited cells. RESULTS/ANTICIPATED RESULTS: We anticipate that CHCHD2 transcriptional adaptation can functionally compensate for the locus loss of function of CHCHD10. This mechanism of transcriptional adaptation may contribute to an explanation for variation in clinical manifestations of patient phenotypes. DISCUSSION/SIGNIFICANCE: Our approach would advance discovery science towards by exploring CHCHD10/2 transcriptional adaptation mechanism that can lead to novel therapies for rare Amyotrophic lateral sclerosis, such as CHCHD10-R15L.

Deficient Sarcolemma Repair in ALS: A Novel Mechanism with Therapeutic Potential.

The plasma membrane (sarcolemma) of skeletal muscle myofibers is susceptible to injury caused by physical and chemical stresses during normal daily movement and/or under disease conditions. These acute plasma membrane disruptions are normally compensated by an intrinsic membrane resealing process involving interactions of multiple intracellular proteins including dysferlin, annexin, caveolin, and Mitsugumin 53 (MG53)/TRIM72. There is new evidence for compromised muscle sarcolemma repair mechanisms in Amyotrophic Lateral Sclerosis (ALS). Mitochondrial dysfunction in proximity to neuromuscular junctions (NMJs) increases oxidative stress, triggering MG53 aggregation and loss of its function. Compromised membrane repair further worsens sarcolemma fragility and amplifies oxidative stress in a vicious cycle. This article is to review existing literature supporting the concept that ALS is a disease of oxidative-stress induced disruption of muscle membrane repair that compromise the integrity of the NMJs and hence augmenting muscle membrane repair mechanisms could represent a viable therapeutic strategy for ALS.

Generation of a heterozygous FUS-Q290X knock in human embryonic stem cell line (WAe009-A-83) using CRISPR/Cas9 system

Fused in Sarcoma (FUS) gene encodes FUS RNA binding protein, a multifunctional protein component of the heterogeneous nuclear ribonucleoprotein complex, which is involved in pre-mRNA splicing and the export of fully processed mRNA to the cytoplasm, and it has been implicated in regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. FUS gene mutations result in amyotrophic lateral sclerosis and Liposarcoma. This heterozygous FUS-Q290X knock in hESC line will be a valuable tool to investigate the disease mechanisms of amyotrophic lateral sclerosis and Liposarcoma.

Biomarkers and molecular mechanisms of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in adults involving non-demyelinating motor disorders. About 90% of ALS cases are sporadic, while 10-12% of cases are due to some genetic reasons. Mutations in superoxide dismutase 1 (SOD1), TAR, c9orf72 (chromosome 9 open reading frame 72) and VAPB genes are commonly found in ALS patients. Therefore, the mechanism of ALS development involves oxidative stress, endoplasmic reticulum stress, glutamate excitotoxicity and aggregation of proteins, neuro-inflammation and defective RNA function. Cholesterol and LDL/HDL levels are also associated with ALS development. As a result, sterols could be a suitable biomarker for this ailment. The main mechanisms of ALS development are reticulum stress, neuroinflammation and RNA metabolism. The multi-nature development of ALS makes it more challenging to pinpoint a treatment.

Brain energy metabolism in ALS: A phosphorus-31 magnetic resonance spectroscopy study

In vitro and animal studies indicate that bioenergetic dysfunction in brain is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS). We aimed to characterise for the first time brain energy metabolism in ALS patients using phosphorus-31 magnetic resonance spectroscopy (31P-MRS).

Delayed Onset Muscle Soreness (DOMS): The Repeated Bout Effect and Chemotherapy-Induced Axonopathy May Help Explain the Dying-Back Mechanism in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.

Delayed onset muscle soreness (DOMS) is hypothesized to be caused by glutamate excitotoxicity-induced acute compression axonopathy of the sensory afferents in the muscle spindle. Degeneration of the same sensory afferents is implicated in the disease onset and progression of amyotrophic lateral sclerosis (ALS). A series of “silent” acute compression proprioceptive axonopathies with underlying genetic/environmental factors, damaging eccentric contractions and the non-resolving neuroinflammatory process of aging could lead to ALS disease progression. Since the sensory terminals in the muscle spindle could not regenerate from the micro-damage in ALS, unlike in DOMS, the induced protective microcircuits and their long-term functional plasticity (the equivalent of the repeated bout effect in DOMS) will be dysfunctional. The acute stress invoking osteocalcin, bradykinin, COX1, COX2, GDNF, PGE2, NGF, glutamate and N-methyl-D-aspartate (NMDA) receptors are suggested to be the critical signalers of this theory. The repeated bout effect of DOMS and the dysfunctional microcircuits in ALS are suggested to involve several dimensions of memory and learning, like pain memory, inflammation, working and episodic memory. The spatial encoding of these memory dimensions is compromised in ALS due to blunt position sense from the degenerating proprioceptive axon terminals of the affected muscle spindles. Dysfunctional microcircuits progressively and irreversibly interfere with postural control, with motor command and locomotor circuits, deplete the neuroenergetic system, and ultimately interfere with life-sustaining central pattern generators in ALS. The activated NMDA receptor is suggested to serve the “gate control” function in DOMS and ALS in line with the gate control theory of pain. Circumvention of muscle spindle-loading could be a choice of exercise therapy in muscle spindle-affected neurodegenerative diseases.

Neurogenic Dysphagia: Systematic Review and Proposal of a Classification System.

Introduction and validation of a phenotypic classification of neurogenic dysphagia based on flexible endoscopic evaluation of swallowing (FEES). A systematic literature review was conducted, searching MEDLINE from inception to May 2020 for FEES findings in neurologic diseases of interest. Based on a retrospective analysis of FEES videos in neurologic diseases and considering the results from the review, a classification of neurogenic dysphagia was developed distinguishing different phenotypes. The classification was validated using 1,012 randomly selected FEES videos of patients with various neurologic disorders. Chi-square tests were used to compare the distribution of dysphagia phenotypes between the underlying neurologic disorders. A total of 159 articles were identified, of which 59 were included in the qualitative synthesis. Seven dysphagia phenotypes were identified: (1) "premature bolus spillage" and (2) "delayed swallowing reflex" occurred mainly in stroke, (3) "predominance of residue in the valleculae" was most common in Parkinson disease, (4) "predominance of residue in the piriform sinus" occurred only in myositis, motoneuron disease, and brainstem stroke, (5) "pharyngolaryngeal movement disorder" was found in atypical Parkinsonian syndromes and stroke, (6) "fatigable swallowing weakness" was common in myasthenia gravis, and (7) "complex disorder" with a heterogeneous dysphagia pattern was the leading mechanism in amyotrophic lateral sclerosis. The interrater reliability showed a strong agreement (kappa = 0.84). Neurogenic dysphagia is not a symptom, but a multietiologic syndrome with different phenotypic patterns depending on the underlying disease. Dysphagia phenotypes can facilitate differential diagnosis in patients with dysphagia of unclear etiology.

Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients.

Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients.Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters.Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging.Results: We found GSH in motor cortex (r = −0.431, p = 0.04) and corticospinal tract (r = −0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = −0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine.Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.

Relationship between Dietary Fiber Intake and the Prognosis of Amytrophic Lateral Sclerosis in Korea.

The gut microbiota has been suggested as an important factor in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether the intake of different kinds of dietary fiber was related to the disease progression rate (∆FS) and survival time. In total, 272 Korean sporadic ALS patients diagnosed according to the revised EI Escorial criteria were recruited starting in March 2011 and were followed until the occurrence of events or the end of September 2020. The events included percutaneous endoscopic gastrostomy, tracheostomy, and death. Dietary fiber intake was calculated based on a 24-h dietary recall and classified according to five major fiber-rich foods: vegetables, fruits, grains, legumes, and nuts/seeds. Among the total participants, the group with ∆FS values lower than the mean ∆FS (0.75) was noted in the highest tertiles of total and vegetable fiber intake. Participants in the highest tertile for vegetable fiber intake showed longer survival in the Kaplan–Meier analysis (p = 0.033). Notably, vegetable fiber intake was negatively correlated with pro-inflammatory cytokine (interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1) levels in the cerebrospinal fluid. This study showed that vegetable fiber intake could influence the disease progression rate and survival time. Further clinical trials are needed to confirm whether dietary fiber supplementation improves the prognosis of ALS.

Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1G93A female mice.

ABSTRACTNeuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1G93A murine model. SOD1G93A mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age (here, postnatal day 60; P60) until study endpoint. Body weight, motor coordination, phenotypic score, disease onset and survival were measured throughout the study, and compared between vehicle- and drug-injected groups. Treatment with the P2X7R antagonist JNJ-47965567 delayed disease onset, reduced body weight loss and improved motor coordination and phenotypic score in female SOD1G93A mice, although it did not increase lifespan. Interestingly, neither beneficial nor detrimental effects were observed in males in any of the analyzed parameters. Treatment did not affect motor neuron survival or ChAT, Iba-1 and P2X7R protein expression in endpoint individuals of mixed sexes. Overall, chronic administration of JNJ-47965567 for 4 times per week to SOD1G93A mice from pre-onset stage altered disease progression in female individuals while it did not have any effect in males. Our results suggest a partial, yet important, effect of P2X7R in the development and progression of ALS.

Insights into amyotrophic lateral sclerosis linked Pro525Arg mutation in the fused in sarcoma protein through in silico analysis and molecular dynamics simulation

A novel heterozygous mutation, Pro525Arg (P525R) in the Fused in Sarcoma (FUS) protein is predominant in young adult females with familial amyotrophic lateral sclerosis (fALS). Investigation of the biophysical characteristics of this mutation through analysis of protein conformation could provide insights into the pathogenic mechanism of amyotrophic lateral sclerosis (ALS). Here, several computational prediction tools were applied to investigate the effect of P525R on the stability, flexibility, and function of FUS. Conservation and biochemical analyses showed that P525 is highly conserved; the mutation of proline to arginine at position 525 in FUS results in a notable increase in molecular weight, number of hydrogen bonds, and loss of hydrophobicity. By performing electrostatic potential, intra-protein interaction, and binding affinity analyses, we found increased electrostatic potential charge in the mutant protein and fewer hydrophobic interactions than the wild-type structure. Binding affinity of the FUS nuclear localization signal (NLS) mutant for transportin (Trn1) was also decreased compared to wild-type. Our molecular dynamics (MD) simulation results highlighted the exchange between hydrophobic and hydrophilic residues from the core to the surface in the mutant structure; also, upon P525R mutation, FUS became less stable, less flexible and more compact and rigid. Overall, this study demonstrated that the Pro525Arg mutation significantly alters the structure and conformation of FUS through loss of nuclear function, thereby likely contributing to its accumulation in the cytoplasm, which has been implicated in the pathogenesis of fALS. Our study can potentially aid in the design of drugs for FUS-associated neurodegenerative diseases.

Reprogramming fibroblasts and peripheral blood cells from a C9ORF72 patient: A proof-of-principle study.

As for the majority of neurodegenerative diseases, pathological mechanisms of amyotrophic lateral sclerosis (ALS) have been challenging to study due to the difficult access to alive patients' cells. Induced pluripotent stem cells (iPSCs) offer a useful in vitro system for modelling human diseases. iPSCs can be theoretically obtained by reprogramming any somatic tissue although fibroblasts (FB) remain the most used cells. However, reprogramming peripheral blood cells (PB) may offer significant advantages. In order to investigate whether the choice of starting cells may affect reprogramming and motor neuron (MNs) differentiation potential, we used both FB and PB from a same C9ORF72‐mutated ALS patient to obtain iPSCs and compared several hallmarks of the pathology. We found that both iPSCs and MNs derived from the two tissues showed identical properties and features and can therefore be used interchangeably, giving the opportunity to easily obtain iPSCs from a more manageable source of cells, such as PB.

Molecular mechanism of amyotrophic lateral sclerosis (ALS) from the viewpoint of the formation and degeneration of transactive response DNA-binding protein 43 kDa (TDP-43) inclusions

Sporadic amyotrophic lateral sclerosis (SALS) and many cases of familial ALS (FALS) demonstrate cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusion bodies. Thus, TDP-43 plays a vital role in ALS pathogenesis. Functional analysis of the ALS causative genes advanced the elucidation of the mechanism associated with the formation and degradation of TDP-43 aggregates. Stress granules, which are non-membranous organelles, are attracting attention as sites of aggregate formation, with involvement of FUS and C9orf72. Concurrently, ALS causative genes related to the ubiquitin-proteasome and autophagy systems, which are aggregate degradation mechanisms, have also been reported. Therefore, therapeutic research based on the molecular pathology common to SALS and FALS has been advanced.