Selective striatal mtDNA depletion in end-stage Huntington's disease R6/2 mice

Hering, Tanja; Birth, Nathalie; Taanman, Jan‐Willem; Orth, Michael

doi:10.1016/j.expneurol.2015.02.004

Cited by 21 publications

(28 citation statements)

References 62 publications

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“…In wildtype mice, PGC-1α mRNA levels were identical in striatum and cortex, but mitochondrial/nuclear DNA ratios (mtDNA/nDNA) and citrate synthase activity were higher in the striatum (Hering et al, 2015;Pickrell et al, 2011). Interestingly, in R6/2 HD mice, PGC-1α mRNA levels were similarly decreased in the striatum and cortex; however, only the striatum presented decreased mtDNA/nDNA (Hering et al, 2015), suggesting that the striatum may be particularly susceptible to reduced PGC-1α expression. In early-stage HD patients, PGC-1α mRNA levels were decreased in the striatum (caudate nucleus), but not in the hippocampus or cerebellum Weydt et al, 2006).…”

Section: Mitochondrial Biogenesismentioning

confidence: 82%

“…More recently, PGC-1α suppression in cultured neurons was found to contribute to mHtt-induced increases in extrasynaptic NMDAR activity and vulnerability to excitotoxic insults (Puddifoot et al, 2012). In wildtype mice, PGC-1α mRNA levels were identical in striatum and cortex, but mitochondrial/nuclear DNA ratios (mtDNA/nDNA) and citrate synthase activity were higher in the striatum (Hering et al, 2015;Pickrell et al, 2011). Interestingly, in R6/2 HD mice, PGC-1α mRNA levels were similarly decreased in the striatum and cortex; however, only the striatum presented decreased mtDNA/nDNA (Hering et al, 2015), suggesting that the striatum may be particularly susceptible to reduced PGC-1α expression.…”

Section: Mitochondrial Biogenesismentioning

confidence: 95%

“…It is presently unclear whether defective complex assembly contributes for HD pathology. Indeed, whereas one study reported defective complex II assembly and activity in striatal mitochondria from mice injected with N-terminal mHtt (Damiano et al, 2013), another study reported normal assembly and activity of respiratory complexes in striatal and cortical mitochondria from R6/2 mice (Hering et al, 2015). Nevertheless, other lines of evidence suggest that the direct interaction between mHtt and neuronal mitochondria is a relevant component of HD pathology, contributing to calcium handling defects (Panov et al, 2002), disrupted mitochondrial trafficking (Orr et al, 2008) and excessive mitochondrial fission (Song et al, 2011).…”

Section: Mitochondrial Biogenesismentioning

confidence: 95%

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Mitochondrial dynamics and quality control in Huntington's disease

Guedes-Dias

Pinho

Soares

et al. 2016

Neurobiology of Disease

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Huntington's disease (HD) is an inherited neurodegenerative disorder caused by polyglutamine expansion mutations in the huntingtin protein. Despite its ubiquitous distribution, expression of mutant huntingtin (mHtt) is particularly detrimental to medium spiny neurons within the striatum. Mitochondrial dysfunction has been associated with HD pathogenesis. Here we review the current evidence for mHtt-induced abnormalities in mitochondrial dynamics and quality control, with a particular focus on brain and neuronal data pertaining to striatal vulnerability. We address mHtt effects on mitochondrial biogenesis, protein import, complex assembly, fission and fusion, mitochondrial transport, and on the degradation of damaged mitochondria via autophagy (mitophagy). For an integrated perspective on potentially converging pathogenic mechanisms, we also address impaired autophagosomal transport and abnormal mHtt proteostasis in HD.

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Section: Mitochondrial Biogenesismentioning

confidence: 82%

Section: Mitochondrial Biogenesismentioning

confidence: 95%

Section: Mitochondrial Biogenesismentioning

confidence: 95%

See 1 more Smart Citation

Mitochondrial dynamics and quality control in Huntington's disease

Guedes-Dias

Pinho

Soares

et al. 2016

Neurobiology of Disease

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“…Briefly, relative quantification was performed by calculating the ratio between the cycle numbers of the threshold within the logarithmic phase of the gene of interest relative to that of the reference genes. Methionyl aminopeptidase 1 ( Metap1 , polymerase (RNA) II (DNA directed) polypeptide A ( Polr2a ) and hypoxanthine guanine phosphoribosyl transferase ( Hprt ) were chosen as reference genes for heart muscle, brain and liver [26, 27]. For analysis of gastrocnemius muscle data Metap1 and Polr2a were chosen as reference genes with a heterogeneous stability.…”

Section: Methodsmentioning

confidence: 99%

High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington’s disease expansion mutation carriers shows normal mitochondrial respiratory function

et al. 2017

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Alterations in mitochondrial respiration are an important hallmark of Huntington’s disease (HD), one of the most common monogenetic causes of neurodegeneration. The ubiquitous expression of the disease causing mutant huntingtin gene raises the prospect that mitochondrial respiratory deficits can be detected in skeletal muscle. While this tissue is readily accessible in humans, transgenic animal models offer the opportunity to cross-validate findings and allow for comparisons across organs, including the brain. The integrated respiratory chain function of the human vastus lateralis muscle was measured by high-resolution respirometry (HRR) in freshly taken fine-needle biopsies from seven pre-manifest HD expansion mutation carriers and nine controls. The respiratory parameters were unaffected. For comparison skeletal muscle isolated from HD knock-in mice (HdhQ111) as well as a broader spectrum of tissues including cortex, liver and heart muscle were examined by HRR. Significant changes of mitochondrial respiration in the HdhQ knock-in mouse model were restricted to the liver and the cortex. Mitochondrial mass as quantified by mitochondrial DNA copy number and citrate synthase activity was stable in murine HD-model tissue compared to control. mRNA levels of key enzymes were determined to characterize mitochondrial metabolic pathways in HdhQ mice. We demonstrated the feasibility to perform high-resolution respirometry measurements from small human HD muscle biopsies. Furthermore, we conclude that alterations in respiratory parameters of pre-manifest human muscle biopsies are rather limited and mirrored by a similar absence of marked alterations in HdhQ skeletal muscle. In contrast, the HdhQ111 murine cortex and liver did show respiratory alterations highlighting the tissue specific nature of mutant huntingtin effects on respiration.

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“…The pathomechanism likely involves a combination of effects, for instance on vesicular transport, endocytosis, the ubiquitin-proteasome system and transcription [6, 7]. A number of studies indicate mitochondrial dysfunction as an important contributor to the pathology [8–14]. In addition several results point to altered Ca 2+ homeostasis and excitotoxicity in affected neurons [15, 16].…”

Section: Introductionmentioning

confidence: 99%

Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

et al. 2016

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Huntington´s disease (HD) is a hereditary neurodegenerative disease resulting from an expanded polyglutamine sequence (poly-Q) in the protein huntingtin (HTT). Various studies report atrophy and metabolic pathology of skeletal muscle in HD and suggest as part of the process a fast-to-slow fiber type transition that may be caused by the pathological changes in central motor control or/and by mutant HTT in the muscle tissue itself. To investigate muscle pathology in HD, we used R6/2 mice, a common animal model for a rapidly progressing variant of the disease expressing exon 1 of the mutant human gene. We investigated alterations in the extensor digitorum longus (EDL), a typical fast-twitch muscle, and the soleus (SOL), a slow-twitch muscle. We focussed on mechanographic measurements of excised muscles using single and repetitive electrical stimulation and on the expression of the various myosin isoforms (heavy and light chains) using dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole muscle and single fiber preparations. In EDL of R6/2, the functional tests showed a left shift of the force-frequency relation and decrease in specific force. Moreover, the estimated relative contribution of the fastest myosin isoform MyHC IIb decreased, whereas the contribution of the slower MyHC IIx isoform increased. An additional change occurred in the alkali MyLC forms showing a decrease in 3f and an increase in 1f level. In SOL, a shift from fast MyHC IIa to the slow isoform I was detectable in male R6/2 mice only, and there was no evidence of isoform interconversion in the MyLC pattern. These alterations point to a partial remodeling of the contractile apparatus of R6/2 mice towards a slower contractile phenotype, predominantly in fast glycolytic fibers.

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Selective striatal mtDNA depletion in end-stage Huntington's disease R6/2 mice

Cited by 21 publications

References 62 publications

Mitochondrial dynamics and quality control in Huntington's disease

Mitochondrial dynamics and quality control in Huntington's disease

High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington’s disease expansion mutation carriers shows normal mitochondrial respiratory function

Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

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