Bioenergetic abnormalities in discrete cerebral motor pathways presage spinal cord pathology in the G93A SOD1 mouse model of ALS

Browne, Susan; Yang, Le; DiMauro, Jon-Paul; Fuller, Sara W.; Licata, Stephanie C.; Beal, M. Flint

doi:10.1016/j.nbd.2006.01.001

Cited by 148 publications

(117 citation statements)

References 60 publications

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“…25 In vivo autoradiography studies in SOD1 mice have also demonstrated that glucose utilization is impaired in motor tracts before any pathologic alterations and that this is accompanied by ATP depletion. 26 Metabolic alterations favouring lactacidosis may also be triggered directly as a consequence of Ca 2 þ -mediated excitotoxicity and glutamate excitotoxicity. 16 Metabolic acidosis may be furthermore reinforced during disease progression by respiratory failure and subsequent respiratory acidosis, a condition that correlates with poor prognosis in ALS patients.…”

Section: Discussionmentioning

confidence: 99%

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

et al. 2013

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca 2 þ overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1 G93A ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS. Cell Death and Differentiation (2013) 20, 589-598; doi:10.1038/cdd.2012.158; published online 11 January 2013Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition where motoneurons in the spinal cord and brain stem die, resulting in paralysis and eventual death. Despite the significant recent advances in understanding the pathophysiology and genetics of ALS, 1 there is no cure for this condition. Currently, the only FDA-approved, disease-modifying drug used for the treatment of ALS is riluzole, which inhibits neuronal glutamate, releases and stimulates glutamate uptake into astrocytes. 2 The use of riluzole is based on the hypothesis that overactivation of Ca 2 þ -permeable AMPA receptors in motoneurons results in excitotoxicity, and that this process contributes to motoneuron death in ALS. 3 Nevertheless, the disease-modifying effects of riluzole therapy are moderate and vary among patients. 4 Acid-sensing ion channels (ASICs) represent a group of ion channels activated by protons. They belong to the epithelial sodium (Na þ ) family of amiloride-sensitive cation channels, and allow for Na þ and Ca 2 þ entry into neurons. Of the six ASIC subunits cloned, ASIC1a, ASIC2a and ASIC2b are expressed in the brain and spinal cord neurons. 5 ASIC1a and ASIC2s are found in the brain regions with high synaptic density and facilitate excitatory synaptic transmission. 6,7 ASIC1a in particular is involved in nociception and fear behavior triggered by hypercapnia. 8,9 ASICs have also been investigated as new targets for the treatment of ischemic stroke and cerebral hypoxia 10 on the premise that activation of ASIC1a during ischemia ...

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Section: Discussionmentioning

confidence: 99%

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

et al. 2013

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“…Glucose utilization (35) and monocarboxylate transporter 1 (MCT1)-mediated lactate uptake (36) within the CNS are inhibited by acidosis. Indeed, glucose uptake and/or levels within the CNS are significantly diminished in patients with ALS (37), SOD1 G93A mice (32,38), and in WT mice exposed to cerebrospinal fluid (CSF) from patients with ALS (39). Moreover, lactate levels are reduced in spinal cords of SOD1 G93A mice (19), as is the expression of MCT1 (36).…”

Section: Discussionmentioning

confidence: 99%

Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

Dodge¹,

Treleaven²,

Fidler³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H + concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral α-glucosidase activities. Disease-related changes in glycogen, glucose, and α-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.

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“…In fact, caloric restriction, which activates AMPK (Baur et al, 2006;Curtis et al, 2006), further shortens lifespan and accelerates disease progression (Hamadeh et al, 2005;Mattson et al, 2007;Patel et al, 2010). On the contrary, feeding mSOD1 mice a high-energy diet remarkably increases lifespan, improves locomotor behavior, increases fat stores, and protects motor neurons (Dupuis et al, 2004;Browne et al, 2006;Zhao et al, 2006). AMPK activation may be initially beneficial to turn on catabolic pathways that can increase ATP levels and therefore restore energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

et al. 2012

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A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMPactivated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK ␣2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease.

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Bioenergetic abnormalities in discrete cerebral motor pathways presage spinal cord pathology in the G93A SOD1 mouse model of ALS

Cited by 148 publications

References 60 publications

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

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