Mitochondrial oxidative metabolism in motor neuron degeneration (<i>mnd</i>) mouse central nervous system

Bertamini, M.; Mora, Barbara; Guarneri, Rosa; Guarneri, P.; Bigini, Paolo; Mennini, Tiziana; Curti, Daniela

doi:10.1046/j.1460-9568.2002.02299.x

Cited by 42 publications

(14 citation statements)

References 33 publications

(29 reference statements)

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“…Spinal Cord OXPHOS Enzyme Activities-Frozen spinal cord was homogenized with a Teflon glass homogenizer in 10 vol: weight homogenization buffer (320 mM sucrose, 10 mM HEPES, 1 mM EGTA, pH 7.4) (19). A portion of the homogenate was separated into aliquots, snap-frozen in liquid nitrogen, and stored at Ϫ80°C for complex I (NADH:ubiquinone oxidoreductase) and complex III (ubiquinol:cytochrome c oxidoreductase) activity assays and for protein assays.…”

Section: Methodsmentioning

confidence: 99%

Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein

Son

Leary

Romain

et al. 2008

Journal of Biological Chemistry

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G93A SOD1 transgenic mice overexpressing CCS protein develop an accelerated disease course that is associated with enhanced mitochondrial pathology and increased mitochondrial localization of mutant SOD1. Because these results suggest an effect of mutant SOD1 on mitochondrial function, we assessed the enzymatic activities of mitochondrial respiratory chain complexes in the spinal cords of CCS/G93A SOD1 and control mice. CCS/G93A SOD1 mouse spinal cord demonstrates a 55% loss of complex IV (cytochrome c oxidase) activity compared with spinal cord from age-matched non-transgenic or G93A SOD1 mice. In contrast, CCS/G93A SOD1 spinal cord shows no reduction in the activities of complex I, II, or III. Blue native gel analysis further demonstrates a marked reduction in the levels of complex IV but not of complex I, II, III, or V in spinal cords of CCS/G93A SOD1 mice compared with nontransgenic, G93A SOD1, or CCS/WT SOD1 controls. With SDS-PAGE analysis, spinal cords from CCS/G93A SOD1 mice showed significant decreases in the levels of two structural subunits of cytochrome c oxidase, COX1 and COX5b, relative to controls. In contrast, CCS/G93A SOD1 mouse spinal cord showed no reduction in levels of selected subunits from complexes I, II, III, or V. Heme A analyses of spinal cord further support the existence of cytochrome c oxidase deficiency in CCS/G93A SOD1 mice. Collectively, these results establish that CCS/G93A SOD1 mice manifest an isolated complex IV deficiency which may underlie a substantial part of mutant SOD1-induced mitochondrial cytopathy.

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Section: Methodsmentioning

confidence: 99%

Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein

Son

Leary

Romain

et al. 2008

Journal of Biological Chemistry

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“…ALCAR treatment ameliorates mitochondrial dysfunction caused by a variety of neurotoxic insults (Virmani et al, 1995(Virmani et al, , 2005Bertamini et al, 2002;Hart et al, 2004a;Sayed-Ahmed et al, 2004;Calabrese et al, 2005;Binienda et al, 2006;Mansour, 2006;Wang et al, 2007). Paclitaxel also causes degeneration of the sensory neurons' intraepidermal terminal arbors, without degeneration of the parent axons in the peripheral nerve, and it activates cutaneous Langerhans cells .…”

Section: Introductionmentioning

confidence: 99%

Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells

Jin

Flatters

Xiao

et al. 2008

Experimental Neurology

142

132

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Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria.

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“…How the mutations predispose to increased sensitivity to apoptosis is still unknown and various mechanisms may be involved. Increased oxyradicals and lipid peroxides indicate that oxidative metabolism is altered in the mnd mouse [Bertamini et al, 2002;Guarneri et al, 2004], with decreased activity of several mitochondrial respiratory complexes in the spinal cord [Bertamini et al, 2002;Guarneri et al, 2004]. Alterations in CLN8 might therefore act by enhancing the damaging effects of these events.…”

Section: Discussionmentioning

confidence: 99%

A novelCLN8mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function

et al. 2009

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The late-infantile-onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes. Homozygous mutations in CLN8 are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR), first identified in Finland; and a variant of late-infantile NCL (v-LINCL) described in a subset of Turkish and Italian patients. The function of the protein encoded by CLN8 is currently unknown. Here we report the identification of an Italian v-LINCL patient with a complete isodisomy of chromosome 8, leading to homozygosity of a maternally-inherited 3-bp deletion in CLN8 gene (c.180_182delGAA, p.Lys61del). Notably, uniparental disomy (UPD) has never been described associated with the NCLs. In addition, we provide evidence of the biological role of CLN8 characterized by expressing in different neuronal cell models the native protein, the protein carrying the mutation identified here, or three additional missense mutations previously described. Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death.

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Mitochondrial oxidative metabolism in motor neuron degeneration (mnd) mouse central nervous system

Cited by 42 publications

References 33 publications

Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein

Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein

Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells

A novelCLN8mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function

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