Role of Mitochondrial Dysfunction in Motor Neuron Degeneration in ALS

Santa-Cruz, Luz Diana; Ramírez-Jarquín, Uri Nimrod; Tapia, Ricardo

doi:10.5772/31290

Cited by 6 publications

(2 citation statements)

References 168 publications

(163 reference statements)

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“…Studies of mitochondrial DNA (mtDNA) cytosine methylation and the Dnmts that regulate mtDNA methylation are not as common as studies of nuclear DNA methylation; moreover, many mitochondrial-based mechanisms of disease have been implicated in amyotrophic lateral sclerosis (ALS) (Beal, 2005; Martin, 2010, 2012; Reddy and Reddy, 2011; Panov et al, 2012; Santa-Cruz et al, 2012), but mtDNA methylation and mitochondrial Dnmts have not been studied in ALS. Earlier work tends to minimize the occurrence and importance of mtDNA cytosine methylation.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS

Wong

Gertz

Chestnut

et al. 2013

Front. Cell. Neurosci.

152

144

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Cytosine methylation is an epigenetic modification of DNA catalyzed by DNA methyltransferases. Cytosine methylation of mitochondrial DNA (mtDNA) is believed to have relative underrepresentation; however, possible tissue and cell differences in mtDNA methylation and relationships to neurodegenerative disease have not been examined. We show by immunoblotting that DNA methyltransferase 3A (Dnmt3a) isoform is present in pure mitochondria of adult mouse CNS, skeletal muscle, and testes, and adult human cerebral cortex. Dnmt1 was not detected in adult mouse CNS or skeletal muscle mitochondria but appeared bound to the outer mitochondrial membrane. Immunofluorescence confirmed the mitochondrial localization of Dnmt3a and showed 5-methylcytosine (5mC) immunoreactivity in mitochondria of neurons and skeletal muscle myofibers. DNA pyrosequencing of two loci (D-loop and 16S rRNA gene) and twelve cytosine-phosphate-guanine (CpG) sites in mtDNA directly showed a tissue differential presence of 5mC. Because mitochondria have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the disease mechanisms are uncertain, we evaluated mitochondrial Dnmt3a and 5mC levels in human superoxide dismutase-1 (SOD1) transgenic mouse models of ALS. Mitochondrial Dnmt3a protein levels were reduced significantly in skeletal muscle and spinal cord at presymptomatic or early disease. Immunofluorescence showed that 5mC immunoreactivity was present in mitochondria of neurons and skeletal myofibers, and 5mC immunoreactivity became aggregated in motor neurons of ALS mice. DNA pyrosequencing revealed significant abnormalities in 16S rRNA gene methylation in ALS mice. Immunofluorescence showed that 5mC immunoreactivity can be sequestered into autophagosomes and that mitophagy was increased and mitochondrial content was decreased in skeletal muscle in ALS mice. This study reveals a tissue-preferential mitochondrial localization of Dnmt3a and presence of cytosine methylation in mtDNA of nervous tissue and skeletal muscle and demonstrates that mtDNA methylation patterns and mitochondrial Dnmt3a levels are abnormal in skeletal muscle and spinal cord of presymptomatic ALS mice, and these abnormalities occur in parallel with loss of myofiber mitochondria.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS

Wong

Gertz

Chestnut

et al. 2013

Front. Cell. Neurosci.

152

144

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“…Although several mechanisms (oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, protein aggregation, RNA metabolism, neuroinflamation, etc.) have been suggested to explain the causes underlying the selective degeneration of MNs, the glutamate-induced excitotoxicity is considered as one of the major pathophysiological factors participating in the development of the disease 3 , 4 .…”

Section: Introductionmentioning

confidence: 99%

Tetanus toxin C-fragment protects against excitotoxic spinal motoneuron degeneration in vivo

Netzahualcoyotzi

Tapia

2018

Sci Rep

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The tetanus toxin C-fragment is a non-toxic peptide that can be transported from peripheral axons into spinal motoneurons. In in vitro experiments it has been shown that this peptide activates signaling pathways associated with Trk receptors, leading to cellular survival. Because motoneuron degeneration is the main pathological hallmark in motoneuron diseases, and excitotoxicity is an important mechanism of neuronal death in this type of disorders, in this work we tested whether the tetanus toxin C-fragment is able to protect MN in the spinal cord in vivo. For this purpose, we administered the peptide to rats subjected to excitotoxic motoneuron degeneration induced by the chronic infusion of AMPA in the rat lumbar spinal cord, a well-established model developed in our laboratory. Because the intraspinal infusion of the fragment was only weakly effective, whereas the i.m. administration was remarkably neuroprotective, and because the i.m. injection of an inhibitor of Trk receptors diminished the protection, we conclude that such effects require a retrograde signaling from the neuromuscular junction to the spinal motoneurons. The protection after a simple peripheral route of administration of the fragment suggests a potential therapeutic use of this peptide to target spinal MNs exposed to excitotoxic conditions in vivo.

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Motor terminal degeneration unaffected by activity changes in SOD1G93A mice; a possible role for glycolysis

Carrasco

Bichler

Rich

et al. 2012

Neurobiology of Disease

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This study examined whether activity is a contributing factor to motor terminal degeneration in mice that overexpress the G93A mutation of the SOD1 enzyme found in humans with inherited motor neuron disease. Previously, we showed that overload of muscles accomplished by synergist denervation accelerated motor terminal degeneration in dogs with hereditary canine spinal muscular atrophy (HCSMA). In the present study, we found that SOD1 plantaris muscles overloaded for 2 months showed no differences of neuromuscular junction innervation status when compared with normally loaded, contralateral plantaris muscles. Complete elimination of motor terminal activity using blockade of sciatic nerve conduction with tetrodotoxin cuffs for 1 month also produced no change of plantaris innervation status. To assess possible effects of activity on motor terminal function, we examined the synaptic properties of SOD1 soleus neuromuscular junctions at a time when significant denervation of close synergists had occurred as a result of natural disease progression. When examined in glucose media, SOD1 soleus synaptic properties were similar to wildtype. When glycolysis was inhibited and ATP production limited to mitochondria, however, blocking of evoked synaptic transmission occurred and a large increase in the frequency of spontaneous mEPCs was observed. Similar effects were observed at neuromuscular junctions in muscle from dogs with inherited motor neuron disease (HCSMA), although significant defects of synaptic transmission exist at these neuromuscular junctions when examined in glucose media, as reported previously. These results suggest that glycolysis compensates for mitochondrial dysfunction at motor terminals of SOD1 mice and HCSMA dogs. This compensatory mechanism may help to support resting and activity-related metabolism in the presence of dysfunctional mitochondria and prolong the survival of SOD1 motor terminals.

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Role of Mitochondrial Dysfunction in Motor Neuron Degeneration in ALS

Cited by 6 publications

References 168 publications

Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS

Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS

Tetanus toxin C-fragment protects against excitotoxic spinal motoneuron degeneration in vivo

Motor terminal degeneration unaffected by activity changes in SOD1G93A mice; a possible role for glycolysis

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