Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis.
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ABSTRACT:
SUBMITTER: Chen S
PROVIDER: S-EPMC5563710 | biostudies-other | 2015 Aug
REPOSITORIES: biostudies-other
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Project description:Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by selective motor neuron degeneration. Abnormal protein aggregation and impaired protein degradation pathways may contribute to the disease pathogenesis. Although it has been reported that autophagy is altered in patients and animal model of ALS, little is known about the role of autophagy in motor neuron degeneration in this disease. Our previous study shows that rapamycin, an MTOR-dependent autophagic activator, accelerates disease progression in the SOD1(G93A) mouse model of ALS. In the present report, we have assessed the role of the MTOR-independent autophagic pathway in ALS by determining the effect of the MTOR-independent autophagic inducer trehalose on disease onset and progression, and on motor neuron degeneration in SOD1(G93A) mice. We have found that trehalose significantly delays disease onset prolongs life span, and reduces motor neuron loss in the spinal cord of SOD1(G93A) mice. Most importantly, we have documented that trehalose decreases SOD1 and SQSTM1/p62 aggregation, reduces ubiquitinated protein accumulation, and improves autophagic flux in the motor neurons of SOD1(G93A) mice. Moreover, we have demonstrated that trehalose can reduce skeletal muscle denervation, protect mitochondria, and inhibit the proapoptotic pathway in SOD1(G93A) mice. Collectively, our study indicated that the MTOR-independent autophagic inducer trehalose is neuroprotective in the ALS model and autophagosome-lysosome fusion is a possible therapeutic target for the treatment of ALS.
| S-EPMC4091147 | biostudies-literature
Project description:Macroautophagy/autophagy dysfunction is associated with many neurodegenerative diseases. TFEB (transcription factor EB), an important molecule that regulates lysosomal and autophagy function, is regarded as a potential target for treating some neurodegenerative diseases. However, the relationship between autophagy dysfunction and spiral ganglion neuron (SGN) degeneration and the role of TFEB in SGN degeneration has not yet been established. Here, we showed that in degenerated SGNs, induced by sensory epithelial cell loss in the cochlea of mice following kanamycin and furosemide administration, the lipofuscin area and oxidative stress level were increased, the nuclear-to-cytoplasmic TFEB ratio was decreased, and the late stage of autophagic flux was impaired. After autophagy dysfunction was partially ameliorated with an MTOR inhibitor, which promoted TFEB translocation into the nucleus from the cytoplasm, we found that the lysosomal deficits were significantly relieved, the oxidative stress level was reduced, and the density of surviving SGNs and auditory nerve fibers was increased. The results in the present study reveal that autophagy dysfunction is an important component of SGN degeneration, and TFEB may be a potential target for attenuating SGN degeneration following sensory epithelial cell loss in the cochlea of mice. Abbreviations: 3-NT: 3-nitrotyrosine; 4-HNE: 4-hydroxynonenal; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; ABR: auditory brainstem response; APP: amyloid beta (A4) precursor protein; CLEAR: coordinated lysosomal expression and regulation; CTSB: cathespin B; CTSD: cathespin D; SAMR1: senescence-accelerated mouse/resistance 1; SAMP8: senescence-accelerated mouse/prone 8; MAPK1/ERK2: mitogen-activated protein kinase 1; MTOR: mechanistic target of rapamycin kinase; SGN: spiral ganglion neuron; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscope; TFEB: transcription factor EB.
| S-EPMC6526833 | biostudies-literature
Project description:BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive death of motor neurons. Although the pathogenesis of ALS remains unclear, several cellular processes are known to be involved, including apoptosis. A previous study revealed the apoptosis-related gene c-Abl to be upregulated in sporadic ALS motor neurons.Methodology/findingsWe investigated the possibility that c-Abl activation is involved in the progression of ALS and that c-Abl inhibition is potentially a therapeutic strategy for ALS. Using a mouse motor neuron cell line, we found that mutation of Cu/Zn-superoxide dismutase-1 (SOD1), which is one of the causative genes of familial ALS, induced the upregulation of c-Abl and decreased cell viability, and that the c-Abl inhibitor dasatinib inhibited cytotoxicity. Activation of c-Abl with a concomitant increase in activated caspase-3 was observed in the lumbar spine of G93A-SOD1 transgenic mice (G93A mice), a widely used model of ALS. The survival of G93A mice was improved by oral administration of dasatinib, which also decreased c-Abl phosphorylation, inactivated caspase-3, and improved the innervation status of neuromuscular junctions. In addition, c-Abl expression in postmortem spinal cord tissues from sporadic ALS patients was increased by 3-fold compared with non-ALS patients.Conclusions/significanceThe present results suggest that c-Abl is a potential therapeutic target for ALS and that the c-Abl inhibitor dasatinib has neuroprotective properties in vitro and in vivo.
| S-EPMC3458026 | biostudies-literature
Project description:Neddylation is essential for cardiomyocyte survival in the presence of oxidative stress, and it participates in autophagy regulation. However, whether MLN4924-an inhibitor of neddylation-exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) remains unknown. In the present study, MLN4924 exerted strong cardioprotective effects, demonstrated by significantly elevated cell viability, a decreased LDH leakage rate, and improved cell morphology following H2O2-induced injury in vitro. MLN4924 also markedly decreased the serum myocardial zymogram level, ameliorated cardiac histopathological alterations, and alleviated left ventricular contractile dysfunction, thus limiting the cardiac infarct size in vivo compared with those in MI/R mice. Amazingly, such action of MLN4924 was abrogated by a combined treatment with the autophagic flux inhibitor, chloroquine. The mRFP-GFP-LC3 assay illustrated that MLN4924 restored the defective autophagic flux via enhancing the autolysosome formation. Notably, the expression levels of Rab7 and Atg5 were markedly up-regulated in MLN4924 treated cells and mice subjected to H2O2 or MI/R, respectively, while knockdown of Sirt1 in cells and heart tissue largely blocked such effect and induced autophagosome accumulation by inhibiting its fusion with lysosomes. Transmission electron microscopic analysis, histopathological assay and TUNEL detection of the heart tissues showed that the absence of Sirt1 blocked the cardioprotective effect of MLN4924 by further exacerbating the impaired autophagic flux during MI/R injury in vivo. Taken together, MLN4924 exhibited the strong cardioprotective action via restoring the impaired autophagic flux in H2O2-induced injury in vitro and in MI/R mice. Our work implicated that Sirt1 played a critical role in autophagosome clearance, likely through up-regulating Rab7 in MI/R.
| S-EPMC8406034 | biostudies-literature
Project description:SIRT1 is an NAD+ -dependent deacetylase that functions in a variety of cells and tissues to mitigate age-associated diseases. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor neurons during aging and amyotrophic lateral sclerosis (ALS). In this study, we show that SIRT1 expression decreases in the spinal cord of wild-type mice during normal aging. Using mouse models either overexpressing or lacking SIRT1 in motor neurons, we found that SIRT1 slows age-related degeneration of motor neurons' presynaptic sites at neuromuscular junctions (NMJs). Transcriptional analysis of spinal cord shows an overlap of greater than 90% when comparing alterations during normal aging with changes during ALS, revealing a substantial upregulation in immune and inflammatory response genes and a downregulation of synaptic transcripts. In addition, overexpressing SIRT1 in motor neurons delays progression to end-stage disease in high copy SOD1G93A mice. Thus, our findings suggest that there are parallels between ALS and aging, and interventions to impede aging may also slow the progression of this devastating disease.
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Project description:Beta-amyloid (A?) burden and impaired neuronal autophagy contribute to secondary brain injury after traumatic brain injury (TBI). 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) treatment has been reported to reduce A? aggregation and rescue behavioral deficits in Alzheimer's disease-like mice. Here, we investigated neuroprotective effects of EPPS in a mouse model of TBI. Mice subjected to controlled cortical impact (CCI) were treated with EPPS (120?mg/kg, orally) immediately after CCI and thereafter once daily for 3 or 7?days. We found that EPPS treatment profoundly reduced the accumulation of beta-amyloid precursor protein (?-APP) and A? over a widespread area detected in the pericontusional cortex, external capsule (EC), and hippocampal CA1 and CA3 at 3?days after TBI, accompanied by significant reduction in the TBI-induced diffuse axonal injury identified by increased immunoreactivity of SMI-32 (an indicator for axonal damage). We also found that EPPS treatment ameliorated the TBI-induced synaptic damage (as reflected by enhanced postsynaptic density 95, PSD-95), and impairment of autophagy flux in the neurons as reflected by reduced autophagy markers (LC3-II/LC3-I ratio and p62/SQSTM1) and increased lysosomal enzyme cathepsin D (CTSD) in neurons detected in the cortex and hippocampal CA1. As a result, EPPS treatment significantly reduced the TBI-induced early neuronal apoptosis (assessed by active caspase-3), and eventually prevented cortical tissue loss and hippocampal neuronal loss at 28?days after TBI. Additionally, we found that inhibition of autophagic flux with chloroquine by decreasing autophagosome-lysosome fusion significantly reversed the decreased expressions of neuronal p62/SQSTM1 and apoptosis by EPPS treatment. These data suggest that the neuroprotection by EPPS is, at least in part, related to improved autophagy flux. Finally, we found that EPPS treatment significantly improved the cortex-dependent motor and hippocampal-dependent cognitive deficits associated with TBI. Taken together, these findings support the further investigation of EPPS as a treatment for TBI.
| S-EPMC6457462 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver metabolic syndrome which affects millions of people worldwide. Recently, improving mitochondrial function and autophagic ability have been proposed as a means to prevent NAFLD. It has been previously described that high-temperature requirement protein A2 (HtrA2/Omi) favors mitochondrial homeostasis and autophagy in hepatocytes. Thus, we explored the effects of HtrA2/Omi on regulating mitochondrial function and autophagy during NAFLD development. High-fat diet (HFD)-induced NAFLD in mice and free fatty acids (FFAs)-induced hepatocytes steatosis in vitro were established. Adeno-associated viruses (AAV) in vivo and plasmid in vitro were used to restore HtrA2/Omi expression. In this study, we reported that HtrA2/Omi expression considerably decreased in liver tissues from the HFD-induced NAFLD model and in L02 cells with FFA-treated. However, restoring HtrA2/Omi ameliorated hepatic steatosis, confirming by improved serum lipid profiles, glucose homeostasis, insulin resistance, histopathological lipid accumulation, and the gene expression related to lipid metabolism. Moreover, HtrA2/Omi also attenuated HFD-mediated mitochondrial dysfunction and autophagic blockage. TEM analysis revealed that liver mitochondrial structure and autophagosome formation were improved in hepatic HtrA2/Omi administration mice compared to HFD mice. And hepatic HtrA2/Omi overexpression enhanced mitochondrial fatty acid β-oxidation gene expression, elevated LC3II protein levels, induced LC3 puncta, and decreased SQSTM1/p62 protein levels. Furthermore, hepatic HtrA2/Omi increased respiratory exchange ratio and heat production in mice. Finally, HtrA2/Omi overexpression by plasmid significantly diminished lipid accumulation, mitochondrial dysfunction, and autophagic inhibition in FFA-treated L02 hepatocytes. Taken together, we demonstrated that HtrA2/Omi was a potential candidate for the treatment of NAFLD via improving mitochondrial functions, as well as restoring autophagic flux.
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Project description:Miz1 is a zinc finger protein that regulates expression of cell cycle inhibitors as part of a complex with Myc. Cell cycle-independent functions of Miz1 are poorly understood. Here, we use a Nestin-Cre transgene to delete an essential domain of Miz1 in the central nervous system (Miz1M-NM-^TPOZNes). Miz1M-NM-^TPOZNes mice display cerebellar neurodegeneration characterized by the progressive loss of Purkinje cells. Chromatin immunoprecipitation sequencing and biochemical analyses show that Miz1 activates transcription upon binding to a non-palindromic sequence present in core promoters. Target genes of Miz1 encode regulators of autophagy and proteins involved in vesicular transport that are required for autophagy. Miz1M-NM-^TPOZ neuronal progenitors and fibroblasts show reduced autophagic flux. Consistently, polyubiquitinated proteins and p62/Sqtm1 accumulate in the cerebella of Miz1M-NM-^TPOZNes mice, characteristic features of defective autophagy. Our data suggest that Miz1 may link cell growth and ribosome biogenesis to the transcriptional regulation of vesicular transport and autophagy. ChIP-Seq with H190 and G18 on an Illumina Genome Analyzer IIx.
2013-09-27 | E-GEOD-48602 | biostudies-arrayexpress
Project description:The most common form of autosomal recessive hereditary spastic paraplegia is caused by mutations in the SPG11/KIAA1840 gene on chromosome 15q. The nature of the vast majority of SPG11 mutations found to date suggests a loss-of-function mechanism of the encoded protein, spatacsin. The SPG11 phenotype is, in most cases, characterized by a progressive spasticity with neuropathy, cognitive impairment and a thin corpus callosum on brain MRI. Full neuropathological characterization has not been reported to date despite the description of >100 SPG11 mutations. We describe here the clinical and pathological features observed in two unrelated females, members of genetically ascertained SPG11 families originating from Belgium and Italy, respectively. We confirm the presence of lesions of motor tracts in medulla oblongata and spinal cord associated with other lesions of the central nervous system. Interestingly, we report for the first time pathological hallmarks of SPG11 in neurons that include intracytoplasmic granular lysosome-like structures mainly in supratentorial areas, and others in subtentorial areas that are partially reminiscent of those observed in amyotrophic lateral sclerosis, such as ubiquitin and p62 aggregates, except that they are never labelled with anti-TDP-43 or anti-cystatin C. The neuropathological overlap with amyotrophic lateral sclerosis, associated with some shared clinical manifestations, opens up new fields of investigation in the physiopathological continuum of motor neuron degeneration.
| S-EPMC5839621 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease. Approximately 20% cases of familial ALS show the mutation in the superoxide dismutase-1 (SOD1) gene. We previously demonstrated that homologue to E6AP carboxyl terminus- (HECT-) type ubiquitin protein E3 ligase (NEDL1) physically bind to mutated SOD1 protein but not wild-type SOD1 and promote the degradation of mutated SOD1 protein through ubiquitin-mediated proteasome pathway. To further understand the role of NEDL1 involved in the pathogenesis of familial ALS, we generated transgenic mice with human NEDL1 cDNA. The transgenic mice with human NEDL1 expression showed motor dysfunctions in rotarod, hanging wire, and footprint pattern examination. Histological studies indicated degeneration of neurons in the lumbar spinal cord and muscle atrophy. The number of activated microglia in the spinal cord of transgenic mice was significantly higher than that of wild-type mice, suggesting that inflammation might be observed in the spinal cord of transgenic mice. In conclusion, these findings suggest that the human NEDL1 transgenic mice might develop ALS-like symptoms, showing signs of motor abnormalities, accompanied with significant reduction in muscle strength.
| S-EPMC2952905 | biostudies-other