Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders.
Ontology highlight
ABSTRACT:
SUBMITTER: Area-Gomez E
PROVIDER: S-EPMC8245424 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of both upper and lower motor neurons (MNs) in the brain, brainstem and spinal cord. The neurodegenerative mechanisms leading to MN loss in ALS are not fully understood. Importantly, the reasons why MNs are specifically targeted in this disorder are unclear, when the proteins associated genetically or pathologically with ALS are expressed ubiquitously. Furthermore, MNs themselves are not affected equally; specific MNs subpopulations are more susceptible than others in both animal models and human patients. Corticospinal MNs and lower somatic MNs, which innervate voluntary muscles, degenerate more readily than specific subgroups of lower MNs, which remain resistant to degeneration, reflecting the clinical manifestations of ALS. In this review, we discuss the possible factors intrinsic to MNs that render them uniquely susceptible to neurodegeneration in ALS. We also speculate why some MN subpopulations are more vulnerable than others, focusing on both their molecular and physiological properties. Finally, we review the anatomical network and neuronal microenvironment as determinants of MN subtype vulnerability and hence the progression of ALS.
| S-EPMC6610326 | biostudies-literature
Project description:ObjectiveTo explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND).MethodsClinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families.ResultsLimb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25-52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified.ConclusionMutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD.
| S-EPMC3908355 | biostudies-literature
Project description:Oculomotor neurons, which regulate eye movement, are resilient to degeneration in the lethal motor neuron disease amyotrophic lateral sclerosis (ALS). It would be highly advantageous if motor neuron resilience could be modeled in vitro. Toward this goal, we generated a high proportion of oculomotor neurons from mouse embryonic stem cells through temporal overexpression of PHOX2A in neuronal progenitors. We demonstrate, using electrophysiology, immunocytochemistry, and RNA sequencing, that in vitro-generated neurons are bona fide oculomotor neurons based on their cellular properties and similarity to their in vivo counterpart in rodent and man. We also show that in vitro-generated oculomotor neurons display a robust activation of survival-promoting Akt signaling and are more resilient to the ALS-like toxicity of kainic acid than spinal motor neurons. Thus, we can generate bona fide oculomotor neurons in vitro that display a resilience similar to that seen in vivo.
| S-EPMC6565614 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that share pathological features, including the aberrant accumulation of ubiquitinated protein inclusions within motor neurons. Previously, we have shown that the sequestration of ubiquitin (Ub) into inclusions disrupts Ub homeostasis in cells expressing ALS-associated variants superoxide dismutase 1 (SOD1), fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43). Here, we investigated whether an ALS/FTD-linked pathogenic variant in the CCNF gene, encoding the E3 Ub ligase Cyclin F (CCNF), also perturbs Ub homeostasis. The presence of a pathogenic CCNF variant was shown to cause ubiquitin-proteasome system (UPS) dysfunction in induced pluripotent stem cell-derived motor neurons harboring the CCNF S621G mutation. The expression of the CCNFS621G variant was associated with an increased abundance of ubiquitinated proteins and significant changes in the ubiquitination of key UPS components. To further investigate the mechanisms responsible for this UPS dysfunction, we overexpressed CCNF in NSC-34 cells and found that the overexpression of both wild-type (WT) and the pathogenic variant of CCNF (CCNFS621G) altered free Ub levels. Furthermore, double mutants designed to decrease the ability of CCNF to form an active E3 Ub ligase complex significantly improved UPS function in cells expressing both CCNFWT and the CCNFS621G variant and were associated with increased levels of free monomeric Ub. Collectively, these results suggest that alterations to the ligase activity of the CCNF complex and the subsequent disruption to Ub homeostasis play an important role in the pathogenesis of CCNF-associated ALS/FTD.
| S-EPMC10652331 | biostudies-literature
Project description:The brain is complex and heterogeneous. Even though numerous independent studies indicate cortical hyperexcitability as a potential contributor to amyotrophic lateral sclerosis (ALS) pathology, the mechanisms that are responsible for upper motor neuron (UMN) vulnerability remain elusive. To reveal the electrophysiological determinants of corticospinal motor neuron (CSMN, a.k.a UMN in mice) vulnerability, we investigated the motor cortex of hSOD1G93A mice at P30 (postnatal day 30), a presymptomatic time point. Glutamate uncaging by laser scanning photostimulation (LSPS) revealed altered dynamics especially within the inhibitory circuitry and more specifically in L2/3 of the motor cortex, whereas the excitatory microcircuits were unchanged. Observed microcircuitry changes were specific to CSMN in the motor column. Electrophysiological evaluation of the intrinsic properties in response to the microcircuit changes, as well as the exon microarray expression profiles of CSMN isolated from hSOD1G93A and healthy mice at P30, revealed the presence of a very dynamic set of events, ultimately directed to establish, maintain and retain the balance at this early stage. Also, the expression profile of key voltage-gated potassium and sodium channel subunits as well as of the inhibitory GABA receptor subunits and modulatory proteins began to suggest the challenges CSMN face at this early age. Since neurodegeneration is initiated when neurons can no longer maintain balance, the complex cellular events that occur at this critical time point help reveal how CSMN try to cope with the challenges of disease manifestation. This information is critically important for the proper modulation of UMNs and for developing effective treatment strategies.
| S-EPMC7248374 | biostudies-literature
Project description:Despite the discovery of many genetic risk factors, the cause of the motor neuron death that drives terminal pathology in Amyotrophic Lateral Sclerosis (ALS) remains unknown. We report that the skeletal muscle of ALS patients secretes exosomal vesicles that are specifically toxic to motor neurons. This could not be attributed to a trivial down-stream consequence of muscle denervation. In a study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) from 67 human subjects, including healthy and disease controls, ALS myotubes had a consistent signature of disrupted exosome biogenesis and RNA-processing, and their exosomes induced shortened, less branched, neurites, greater death, and disrupted localization of RNA and RNA-processing proteins in motor neurons. Toxicity was dependent on presence of the FUS protein, which is highly expressed in recipient motor neurons. As part of this work, we carried out gene expression analysis of myotubes (differentiated myoblasts) comparing ALS against two other motor neuron disorders as disease controls (SBMA, Spinal and bulbar muscular atrophy; and Spinal Muscular Atrophy Type 4, SMA-IV) and healthy controls.
2022-04-19 | GSE122261 | GEO
Project description:Peroxisomes are ubiquitous cell organelles that play an important role in lipid metabolism. Accordingly, peroxisomal disorders, including the peroxisome biogenesis disorders and peroxisomal single-enzyme deficiencies, are associated with aberrant lipid metabolism. Lipidomics is an emerging tool for diagnosis, disease-monitoring, identifying lipid biomarkers, and studying the underlying pathophysiology in disorders of lipid metabolism. In this study, we demonstrate the potential of lipidomics for the diagnosis of peroxisomal disorders using plasma samples from patients with different types of peroxisomal disorders. We show that the changes in the plasma profiles of phospholipids, di- and triglycerides, and cholesterol esters correspond with the characteristic metabolite abnormalities that are currently used in the metabolic screening for peroxisomal disorders. The lipidomics approach, however, gives a much more detailed overview of the metabolic changes that occur in the lipidome. Furthermore, we identified novel unique lipid species for specific peroxisomal diseases that are candidate biomarkers. The results presented in this paper show the power of lipidomics approaches to enable the specific diagnosis of different peroxisomal disorders.
| S-EPMC5959966 | biostudies-literature
Project description:Energy metabolism has been repeatedly linked to amyotrophic lateral sclerosis (ALS). Yet, motor neuron (MN) metabolism remains poorly studied and it is unknown if ALS MNs differ metabolically from healthy MNs. To address this question, we first performed a metabolic characterization of induced pluripotent stem cells (iPSCs) versus iPSC-derived MNs and subsequently compared MNs from ALS patients carrying FUS mutations to their CRISPR/Cas9-corrected counterparts. We discovered that human iPSCs undergo a lactate oxidation-fuelled prooxidative metabolic switch when they differentiate into functional MNs. Simultaneously, they rewire metabolic routes to import pyruvate into the TCA cycle in an energy substrate specific way. By comparing patient-derived MNs and their isogenic controls, we show that ALS-causing mutations in FUS did not affect glycolytic or mitochondrial energy metabolism of human MNs in vitro. These data show that metabolic dysfunction is not the underlying cause of the ALS-related phenotypes previously observed in these MNs.
| S-EPMC6742665 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining the in vivo miRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENT Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.
| S-EPMC5452343 | biostudies-literature
Project description:TAR DNA-binding protein-43 (TDP-43) is known to accumulate in ubiquitinated inclusions of amyotrophic lateral sclerosis affected motor neurons, resulting in motor neuron degeneration, loss of motor functions, and eventually death. Rapamycin, an mTOR inhibitor and a commonly used immunosuppressive drug, has been shown to increase the survivability of Amyotrophic Lateral Sclerosis (ALS) affected motor neurons. Here we present a transgenic, TDP-43-A315T, mouse model expressing an ALS phenotype and demonstrate the presence of ubiquitinated cytoplasmic TDP-43 aggregates with > 80% cell death by 28 days post differentiation in vitro. Embryonic stem cells from this mouse model were used to study the onset, progression, and therapeutic remediation of TDP-43 aggregates using a novel microfluidic rapamycin concentration gradient generator. Results using a microfluidic device show that ALS affected motor neuron survival can be increased by 40.44% in a rapamycin dosage range between 0.4-1.0 µM.
| S-EPMC8438029 | biostudies-literature