Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology.
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ABSTRACT:
SUBMITTER: Ryan EB
PROVIDER: S-EPMC7890413 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mutations in MATR3 have been associated with amyotrophic lateral sclerosis (ALS) as well as a form of distal myopathy termed vocal cord pharyngeal distal myopathy (VCPDM). To begin to understand how mutations in MATR3 may cause disease, here we provide initial characterization of transgenic (Tg) mice expressing human wild-type (WT) MATR3 (MATR3WT) and ALS-mutant F115C MATR3 (MATR3F115C) proteins under the control of the mouse prion promoter (MoPrP). For each construct, we established multiple independent lines of mice that stably transmitted the transgene. Unexpectedly, for all stably-transmitting lines examined, MATR3 transgenic mRNA expression was more robust in muscle, with minimal expression in spinal cord. The levels of transgenic mRNA in muscle did not differ between mice from our lead MATR3F115C line and lead MATR3WT line, but mice from the lead MATR3F115C line had significantly higher levels of MATR3 protein in muscle over the lead MATR3WT line. Mice from the three independent, established lines of MATR3F115C mice developed weakness in both fore- and hind-limbs as early as < 1 months of age; whereas, MATR3WT mice aged to > 20 months were not overtly distinguishable from non-transgenic (NT) littermates based on basic motor phenotype. Muscle of both MATR3WT and MATR3F115C mice showed vacuoles by 2 months of age which worsened by ~ 10 months, but vacuolation was noticeably more severe in MATR3F115C mice. Overall, our results indicate that increasing the levels of MATR3 in muscle can cause pathologic changes associated with myopathy, with MATR3F115C expression causing overt muscle atrophy and a profound motor phenotype. The findings suggest that analysis of muscle pathology in individuals harboring ALS-linked MATR3 mutations should be routinely considered.
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Project description:Glycerophosphodiesterase 5 (GDE5) selectively hydrolyses glycerophosphocholine to choline and is highly expressed in type II fiber-rich skeletal muscles. We have previously generated that a truncated mutant of GDE5 (GDE5dC471) that lacks phosphodiesterase activity and shown that transgenic mice overexpressing GDE5dC471 in skeletal muscles show less skeletal muscle mass than control mice. However, the molecular mechanism and pathophysiological features underlying decreased skeletal muscle mass in GDE5dC471 mice remain unclear. In this study, we characterized the skeletal muscle disorder throughout development and investigated the primary cause of muscle atrophy. While type I fiber-rich soleus muscle mass was not altered in GDE5dC471 mice, type II fiber-rich muscle mass was reduced in 8-week-old GDE5dC471 mice. Type II fiber-rich muscle mass continued to decrease irreversibly in 1-year-old transgenic mice with an increase in apoptotic cell. Adipose tissue weight and blood triglyceride levels in 8-week-old and 1-year-old transgenic mice were higher than those in control mice. This study also demonstrated compensatory mRNA expression of neuromuscular junction (NMJ) components, including nicotinic acetylcholine receptors (α1, γ, and ε subunits) and acetylcholinesterase in type II fiber-rich quadriceps muscles in GDE5dC471 mice. However, we did not observe morphological changes in NMJs associated with skeletal muscle atrophy in GDE5dC471 mice. We also found that HSP70 protein levels are significantly increased in the skeletal muscles of 2-week-old GDE5dC471 mice and in mouse myoblastic C2C12 cells overexpressing GDE5dC471. These findings suggest that GDE5dC471 mouse is a novel model of early-onset irreversible type II fiber-rich myopathy associated with cellular stress.
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Project description:Alpha-motoneurons and muscle fibres are structurally and functionally interdependent. Both cell types particularly rely on endoplasmic reticulum (ER/SR) functions. Mutations of the ER proteins VAPB, SigR1 and HSP27 lead to hereditary motor neuron diseases (MNDs). Here, we determined the expression profile and localization of these ER proteins/chaperons by immunohistochemistry and immunoblotting in biopsy and autopsy muscle tissue of patients with amyotrophic lateral sclerosis (ALS) and other neurogenic muscular atrophies (NMAs) and compared these patterns to mouse models of neurogenic muscular atrophy. Postsynaptic neuromuscular junction staining for VAPB was intense in normal human and mouse muscle and decreased in denervated Nmd2J mouse muscle fibres. In contrast, VAPB levels together with other chaperones and autophagy markers were increased in extrasynaptic regions of denervated muscle fibres of patients with MNDs and other NMAs, especially at sites of focal myofibrillar disintegration (targets). These findings did not differ between NMAs due to ALS and other causes. G93A-SOD1 mouse muscle fibres showed a similar pattern of protein level increases in denervated muscle fibres. In addition, they showed globular VAPB-immunoreactive structures together with misfolded SOD1 protein accumulations, suggesting a primary myopathic change. Our findings indicate that altered expression and localization of these ER proteins and autophagy markers are part of the dynamic response of muscle fibres to denervation. The ER is particularly prominent and vulnerable in both muscle fibres and alpha-motoneurons. Thus, ER pathology could contribute to the selective build-up of degenerative changes in the neuromuscular axis in MNDs.
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Project description:X-linked myotubular myopathy (XLMTM) is a devastating, rare, congenital myopathy caused by mutations in the MTM1 gene, resulting in a lack of or dysfunction of the enzyme myotubularin. This leads to severe perinatal weakness and distinctive muscle pathology. It was originally thought that XLMTM was related to developmental arrest in myotube maturation; however, the generation and characterization of several animal models have significantly improved our understanding of clinical and pathological aspects of this disorder. Myotubularin is now known to participate in numerous cellular processes including endosomal trafficking, excitation-contraction coupling, cytoskeletal organization, neuromuscular junction structure, autophagy, and satellite cell proliferation and survival. The available vertebrate models of XLMTM, which vary in severity from complete absence to reduced functional levels of myotubularin, recapitulate features of the human disease to a variable extent. Understanding how pathological endpoints in animals with XLMTM translate to human patients will be essential to interpret preclinical treatment trials and translate therapies into human clinical studies. This review summarizes the published animal models of XLMTM, including those of zebrafish, mice, and dogs, with a focus on their pathological features as compared to those seen in human XLMTM patients.
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Project description:Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease that causes motor neuron (MN) loss and skeletal muscle paralysis. It is uncertain whether this degeneration of MNs is triggered intrinsically and is autonomous, or if the disease initiating mechanisms are extrinsic to MNs. We hypothesized that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. Some inherited forms of ALS are caused by mutations in the superoxide dismutase-1 (SOD1) gene, that encodes an antioxidant protein, so we created transgenic (tg) mice expressing wild-type-, G37R-, and G93A-human SOD1 gene variants only in skeletal muscle. Presence of human SOD1 (hSOD1) protein in skeletal muscle was verified by western blotting, enzyme activity gels, and immunofluorescence in myofibers and satellite cells. These tg mice developed limb weakness and paresis with motor deficits, limb and chest muscle wasting, diaphragm atrophy, and age-related fatal disease with a lifespan shortening of 10-16%. Brown and white adipose tissue also became wasted. Myofibers of tg mice developed crystalline-like inclusions, individualized sarcomere destruction, mitochondriopathy with vesiculation, DNA damage, and activated p53. Satellite cells became apoptotic. The diaphragm developed severe loss of neuromuscular junction presynaptic and postsynaptic integrity, including decreased innervation, loss of synaptophysin, nitration of synaptophysin, and loss of nicotinic acetylcholine receptor and scaffold protein rapsyn. Co-immunoprecipitation identified hSOD1 interaction with rapsyn. Spinal cords of tg mice developed gross atrophy. Spinal MNs formed cytoplasmic and nuclear inclusions, axonopathy, mitochondriopathy, accumulated DNA damage, activated p53 and cleaved caspase-3, and died. Tg mice had a 40-50% loss of MNs. This work shows that hSOD1 in skeletal muscle is a driver of pathogenesis in ALS, that involves myofiber and satellite cell toxicity, and apparent muscle-adipose tissue disease relationships. It also identifies a non-autonomous mechanism for MN degeneration explaining their selective vulnerability as likely a form of target-deprivation retrograde neurodegeneration.
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Project description:Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.
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Project description:Olfactory dysfunction is common in multiple sclerosis (MS). Olfactory bulb and tract pathology in MS and other demyelinating diseases remain unexplored. A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease (MS; n = 17), neuromyelitis optica [(NMO); n = 3] and acute disseminated encephalomyelitis [(ADEM); n = 7] was compared to neuroinflammatory [herpes simplex virus encephalitis (HSE); n = 3], neurodegenerative [Alzheimer's disease (AD); n = 4] and non-neurologic (n = 8) controls. For each case, olfactory bulbs and/or tracts were stained for myelin, axons and inflammation. Inferior frontal cortex and hippocampus were stained for myelin in a subset of MS and ADEM cases. Olfactory bulb/tract demyelination was frequent in all demyelinating diseases [MS 12/17 (70.6%); ADEM 3/7 (42.9%); NMO 2/3 (66.7%)] but was absent in HSE, AD and non-neurologic controls. Inflammation was greater in the demyelinating diseases compared to non-neurologic controls. Olfactory bulb/tract axonal loss was most severe in MS where it correlated significantly with the extent of demyelination (r = 0.610, P = 0.009) and parenchymal inflammation (r = 0.681, P = 0.003). The extent of olfactory bulb/tract demyelination correlated with that found in the adjacent inferior frontal cortex but not hippocampus. We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early and is highly inflammatory, and is specific to demyelinating disease.
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Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the "dying back" phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs.
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Project description:Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.
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Project description:Coiled-helix coiled-helix domain containing protein 10 (CHCHD10) and its paralogue CHCHD2 belong to a family of twin CX9C motif proteins, most of which localize to the intermembrane space of mitochondria. Dominant mutations in CHCHD10 cause amyotrophic lateral sclerosis (ALS)/frontotemporal dementia, and mutations in CHCHD2 have been associated with Parkinson's disease, but the function of these proteins remains unknown. Here we show that the p.R15L CHCHD10 variant in ALS patient fibroblasts destabilizes the protein, leading to a defect in the assembly of Complex I, impaired cellular respiration, mitochondrial hyperfusion, an increase in the steady-state level of CHCHD2, and a severe proliferation defect on galactose, a substrate that forces cells to synthesize virtually all of their ATP aerobically. CHCHD10 and CHCHD2 appeared together in distinct foci by immunofluorescence analysis and could be quantitatively immunoprecipitated with antibodies against either protein. Blue native polyacrylamide gel electrophoresis analyses showed that both proteins migrated in a high molecular weight complex (220 kDa) in control cells, which was, however, absent in patient cells. CHCHD10 and CHCHD2 levels increased markedly in control cells in galactose medium, a response that was dampened in patient cells, and a new complex (40 kDa) appeared in both control and patient cells cultured in galactose. Re-entry of patient cells into the cell cycle, which occurred after prolonged culture in galactose, was associated with a marked increase in Complex I, and restoration of the oxygen consumption defect. Our results indicate that CHCHD10-CHCHD2 complexes are necessary for efficient mitochondrial respiration, and support a role for mitochondrial dysfunction in some patients with ALS.
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