Oral Treatment with RD2RD2 Impedes Development of Motoric Phenotype and Delays Symptom Onset in SOD1G93A Transgenic Mice.
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ABSTRACT:
SUBMITTER: Post J
PROVIDER: S-EPMC8269060 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neuroinflammation 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.
| S-EPMC7648608 | biostudies-literature
Project description:Accumulating evidence suggests that neuroinflammatory processes are implicated in the initiation and progression of amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated an increase in microgliosis and astrogliosis in the lumbar spinal cord of SOD1G93A transgenic mice before the onset of symptoms, a neuroinflammatory response which correlated with disease progression. Importantly, early stage homeostatic microglia enhanced motor neuron survival, while pro-inflammatory microglia were toxic to motor neurons in the SOD1G93A mice. Recent studies from our group have demonstrated that cromolyn sodium, an FDA approved compound, exerts neuroprotective effects in mouse models of Alzheimer's disease by altering microglial cell activation. Here, we tested the neuroprotective and anti-inflammatory effects of cromolyn sodium in the SOD1G93A mouse model of ALS. Our results indicate that cromolyn sodium treatment significantly delayed the onset of neurological symptoms, and improved deficits in PaGE performance in both male and female mice, however, there was only an effect on survival in female mice. Furthermore, there was a significant increase in motor neuron survival in the lumbar spinal cord as well as a significant decrease in the denervation of the neuromuscular junction of the tibialis anterior muscle in cromolyn treated transgenic SOD1G93A mice. Lastly, cromolyn treatment decreased the expression of pro-inflammatory cytokines/chemokines in the lumbar spinal cord and plasma and decreased mast cell degranulation in the tibialis anterior muscle of transgenic SOD1G93A mice. Together, these findings suggest that cromolyn sodium provides neuroprotection in the SOD1G93A mice by decreasing the inflammatory response.
| S-EPMC6881366 | biostudies-literature
Project description:Background Amyotrophic lateral sclerosis (ALS) is an age-dependent and incurable neurodegenerative disease. It is pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. Previous studies showed that excess copper (Cu) might have a role in ALS etiology. However, the underlying mechanism remains incompletely elucidated. Therefore, we aimed to investigate the neurotoxicity and underlying mechanism of Cu exposure in female ALS mice with SOD1G93A gene mutation. Methods After three months of treatment with low-dose Cu exposure (0.13 PPM copper chloride drinking water), the motor ability was assessed by various behavioral methods, including climbing-pole test, rotarod test, hanging endurance test, grip strength test and gait analysis. Muscle atrophy and fibrosis were evaluated by histopathology. The proliferation of astrocytes and microglia was assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord was determined by Nissl staining and ChAT immunohistochemical staining. Western blotting and proteomics revealed the effect of Cu exposure on mitochondrial protein expression in mice. Results Behavioral tests showed that Cu exposure worsened motor function in SOD1G93A mice. Compared with SOD1G93A transgenic mice, there was no significant difference in the pole-climbing test after Cu exposure (P =0.6156). There were significant changes in rotarod test, hanging endurance test and grip strength test (P =0.0121; P = 0.0085; P =0.0105). At the same time, Cu exposure aggravated muscle fibrosis and the loss of spinal motor neurons (P <0.05) and was associated with neuroinflammation (P <0.05). The proteomic analysis further showed that differentially expressed proteins among wild-type mice (WT), ALS mice, and Cu-treated ALS mice were mainly involved in muscle contraction, ATP metabolic processes, immune responses, peroxisomes, mitochondrial electrons respiratory transport chain, GMP biological processes, and were co-related with disturbances in energy metabolism, which was reflected in mitochondrial dysfunction in ALS mice. In addition, Western Blot showed that Cu exposure decreased the expression of mitochondria-related proteins (P <0.05), which was consistent with the results of proteomic analysis. Conclusions In conclusion, our findings showed that Cu exposure aggravates motor dysfunction and pathological changes in ALS mice via mitochondrial dysfunction.
2023-01-29 | PXD039728 |
Project description:AimsTo assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein.MethodsMice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre-symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA-seq was used to compare the spinal cord transcriptomes of wild-type, untreated, and DF402-treated FUS transgenic mice.ResultsDF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre-symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern.ConclusionDF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.
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Project description:Cellular heparan sulfate (HS) has a dual role in scrapie pathogenesis; it is required for PrP(Sc) (scrapie prion protein) formation and facilitates infection of cells, mediating cellular uptake of prions. We examined the involvement of heparanase, a mammalian endoglycosidase degrading HS, in scrapie infection. In cultured cells, heparanase treatment or over-expression resulted in a profound decrease in PrP(Sc). Moreover, disease onset and progression were dramatically delayed in scrapie infected transgenic mice over-expressing heparanase. Together, our results provide direct in vivo evidence for the involvement of intact HS in the pathogenesis of prion disease and the protective role of heparanase both in terms of susceptibility to infection and disease progression.
| S-EPMC4532585 | biostudies-literature
Project description:BackgroundThere is increasing evidence that Parkinson's disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use a transgenic A30P-α-synuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest.MethodsBased on a gait analysis and striatal dopamine levels, we defined 2-month-old A30P mice as pre-symptomatic (psA30P), since they are not showing any motoric impairments of the skeletal neuromuscular system and no reduced dopamine levels, but an intestinal α-synuclein pathology. Mice at this particular age were further used to analyze functional and molecular alterations in both, the gastrointestinal tract and the ENS, to identify early pathological changes. We examined the gastrointestinal motility, the molecular composition of the ENS, as well as the expression of regulating miRNAs. Moreover, we applied A30P-α-synuclein challenges in vitro to simulate PD in the ENS.ResultsA retarded gut motility and early molecular dysregulations were found in the myenteric plexus of psA30P mice. We found that i.e. neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are significantly altered in the psA30P, thus representing potential biomarkers for early PD. Many of the dysregulated miRNAs found in the psA30P mice are reported to be changed in PD patients as well, either in blood, cerebrospinal fluid or brain tissue. Interestingly, the in vitro approaches delivered similar changes in the ENS cultures as seen in the transgenic animals, thus confirming the data from the mouse model.ConclusionsThese findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.
| S-EPMC8170976 | biostudies-literature
Project description:BackgroundWhile reports of mobility problems are common with aging, their relationship to new onset of slow gait is unknown. Our objective was to examine the validity of subjective motoric complaints for predicting the incidence of slow gait.MethodsAmbulatory community-residing participants (mean age 76.6, 55% women) with gait speeds in the normal range enrolled in an aging cohort. Five subjective motoric complaints were assessed. Incident slow gait (walking speed 1 SD below age and sex means) was the primary outcome.ResultsOf the 548 participants at baseline, 90 had prevalent slow gait and 253 participants (73.7%) reported one or more subjective motoric complaints. Subjective motoric complaints were more common in women than men (1.78 vs 1.23). Over a median follow-up of 3.34 years, 68 participants developed new onset slow gait. All 5 questions predicted incident slow gait (adjusted hazard ratios varying from 2.26 to 4.44). More subjective motoric complaints were associated with increased risk of developing incident slow gait (hazard ratio per complaint 1.81). Predictive validity of subjective motoric complaints for incident slow gait was unchanged when using alternate outcome definitions, accounting for diagnostic misclassification, recall bias, or adjusting for multiple confounders.ConclusionsSubjective motoric complaints are a harbinger of mobility disability, and can help improve clinical risk assessments and identify high-risk individuals for interventions to prevent onset of slow gait.
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Project description:Complex I (also known as NADH-ubiquinone oxidoreductase) deficiency is the most frequent mitochondrial disorder present in childhood. NADH-ubiquinone oxidoreductase iron-sulfur protein 3 (NDUFS3) is a catalytic subunit of the mitochondrial complex I; NDUFS3 is conserved from bacteria and essential for complex I function. Mutations affecting complex I, including in the Ndufs3 gene, cause fatal neurodegenerative diseases, such as Leigh syndrome. No treatment is available for these conditions. We developed and performed a detailed molecular characterization of a neuron-specific Ndufs3 conditional KO mouse model. We showed that deletion of Ndufs3 in forebrain neurons reduced complex I activity, altered brain energy metabolism, and increased locomotor activity with impaired motor coordination, balance, and stereotyped behavior. Metabolomics analyses showed an increase of glycolysis intermediates, suggesting an adaptive response to the complex I defect. Administration of metformin to these mice delayed the onset of the neurological symptoms but not of neuronal loss. This improvement was likely related to enhancement of glucose uptake and utilization, which are known effects of metformin in the brain. Despite reports that metformin inhibits complex I activity, our findings did not show worsening a complex I defect nor increases in lactic acid, suggesting that metformin should be further evaluated for use in patients with mitochondrial encephalopathies.
| S-EPMC7710273 | biostudies-literature
Project description:Amyotrophic Lateral Sclerosis (ALS) is a disease in which physical activity plays a controversial role. Epidemiological studies indicate an association between intense exercise and risk of developing ALS. To study the impact of physical activity on ALS, mouse models rely mostly on forced exercise. In this study we hypothesized that voluntary wheel running could represent a better model of the influence of exercise in the pathogenesis of ALS. We used an automated home-cage running-wheel system that enables individual monitoring of performance. To verify the effect of voluntary running on disease progression, prognosis and survival as well as motor functions, we challenged SOD1G93A low-copy male and female mice on one (1 RW, at age 24 weeks) or multiple (3 RW) running sessions at age 13, 18, and 24 weeks. In parallel we measured performance on Rotarod and Grip strength tests at different ages. Several parameters were analyzed through Principal Component Analysis in order to detect what indices correlate and may be useful for deeper understanding of the relation between exercise and disease development. We found mutant male mice more negatively affected than females by prolonged and repeated exercise. SOD1G93A low-copy male mice showed shorter survival, increased body weight loss and poorer disease prognosis when exposed to multiple running sessions. These findings could encourage the investigation of the pathogenetic mechanisms underlying the supposedly increased risk to develop ALS in humans engaged in specific and intense exercise activities.
| S-EPMC6243076 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the central nervous system (CNS). Mutations in the metalloenzyme SOD1 are associated with inherited forms of ALS and cause a toxic gain of function thought to be mediated by dimer destabilization and misfolding. SOD1 binds two Cu and two Zn ions in its homodimeric form. We have applied native ambient mass spectrometry imaging to visualize the spatial distributions of intact metal-bound SOD1G93A complexes in SOD1G93A transgenic mouse spinal cord and brain sections and evaluated them against disease pathology. The molecular specificity of our approach reveals that metal-deficient SOD1G93A species are abundant in CNS structures correlating with ALS pathology whereas fully metalated SOD1G93A species are homogenously distributed. Monomer abundance did not correlate with pathology. We also show that the dimer-destabilizing post-translational modification, glutathionylation, has limited influence on the spatial distribution of SOD1 dimers.
| S-EPMC11310518 | biostudies-literature