Altered macroautophagy in the spinal cord of SOD1 mutant mice

Liang, Li; Zhang, Xiaojie; Le, Weidong

doi:10.4161/auto.5524

Cited by 161 publications

(117 citation statements)

References 21 publications

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“…Indeed, we observed increased levels of LC3II across disease progression corresponding with previous literature (Morimoto et al 2007, Li et al 2008, Tian et al 2011). Similarly we found elevated ULK1 phosphorylation at PND 90, suggesting that AMPK may signal cytoprotective mechanisms such as the clearance of protein aggregates (Hetz et al 2009, Crippa et al 2010.…”

Section: Discussionsupporting

confidence: 90%

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

Coughlan

Mitchem

Hogg

et al. 2015

Neurobiology of Aging

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Section: Discussionsupporting

confidence: 90%

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

Coughlan

Mitchem

Hogg

et al. 2015

Neurobiology of Aging

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“…Dysfunction of the autophagylysosome system may contribute to neuronal degeneration in several neurodegenerative diseases [6,8,9] . Our previous study and those of others have shown the accumulation of autophagic vacuoles in the spinal cord of SOD1 G93A mice and ALS patients, suggesting a role of autophagy in the pathogenesis of ALS [5,10] . We further reported that targeting autophagy with rapamycin, a classic autophagy activator, significantly exacerbates motor neuron loss and fails to Neurosci Bull August 1, 2015, 31 (4): [459][460][461][462][463][464][465][466][467][468] 460 remove the abnormal mutant SOD1 aggregates, raising the possibility of autophagic flux defects in SOD1 G93A mice [11] .…”

Section: Introductionsupporting

confidence: 56%

“…In this study, mice overexpressing the G93A mutation of SOD1 were used to model ALS. The underlying pathogenic mechanisms, although still largely unknown, probably involve the aggregation of misfolded proteins [5,6] .…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

Chen

Zhang

et al. 2015

Neurosci. Bull.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons. Abnormal protein aggregation and impaired protein degradation are believed to contribute to the pathogenesis of this disease. Our previous studies showed that an autophagic flux defect is involved in motor neuron degeneration in the SOD1 G93A mouse model of ALS. Histone deacetylase 6 (HDAC6) is a class II deacetylase that promotes autophagy by inducing the fusion of autophagosomes to lysosomes. In the present study, we showed that HDAC6 expression was decreased at the onset of disease and became extremely low at the late stage in ALS mice. Using lentivirus-HDAC6 gene injection, we found that HDAC6 overexpression prolonged the lifespan and delayed the motor neuron degeneration in ALS mice. Moreover, HDAC6 induced the formation of autolysosomes and accelerated the degradation of SOD1 protein aggregates in the motor neurons of ALS mice. Collectively, our results indicate that HDAC6 has neuroprotective effects in an animal model of ALS by improving the autophagic flux in motor neurons, and autophagosome-lysosome fusion might be a therapeutic target for ALS.

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“…Dysregulation of autophagy has been reported to contribute to ALS pathology both in human patients and animal models [44,57]. Li et al [58] reported a progressive increase of the relative amount of LC3b II from 90 to 140 days of age in SOD1 G93A mice, accompanied by accumulation of autophagic vesicles. These findings could be the result of autophagic flux impairment.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

et al. 2014

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Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1 G93A ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests.We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1 G93A mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1 G93A spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

show abstract

Altered macroautophagy in the spinal cord of SOD1 mutant mice

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative

Cited by 161 publications

References 21 publications

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

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