Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome

Napoli, Eleonora; Ross-Inta, Catherine; Wong, Shirley; Omanska-Klusek, Alicja; Barrow, Cedrick; Iwahashi, Christine; Garcia-Arocena, Dolores; Sakaguchi, Danielle; Berry‐Kravis, Elizabeth; Hagerman, Randi J.; Hagerman, Paul J.; Giulivi, Cecilia R

doi:10.1093/hmg/ddr211

Cited by 100 publications

(168 citation statements)

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“…However, another putative marker for mitochondrial mass, mtDNA copy number per cell, was significantly increased in granulocytes from children with autism (1.5-fold of that from TD children 1 ; Supplemental Table 4). Increased mtDNA copy number without increases in OXPHOS capacity and/or mitochondrial mass, as observed in this study, has been attributed to a cellular response to cope with oxidative stress 35 in an attempt to sustain adequate levels of mitochondrial transcripts from wild-type mtDNA. 36 Consistent with this view, an increased mean mitochondrial ROS production (1.6-fold; Table 1) and increased mtDNA deletions in the segment encoding for cytochrome b (CYTB) but not in that encoding for NADH dehydrogenase subunit 4 (ND4) were observed in granulocytes from children with autism (Table 1, Supplemental Table 4).…”

supporting

confidence: 60%

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

Napoli¹,

Wong²,

Hertz‐Picciotto

et al. 2014

Pediatrics

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103

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Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst were evaluated in granulocytes from age-, race-, and gender-matched children with autism with severity scores of $7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing $1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children' s mean values) of the nuclear factor erythroid 2-related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network.

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supporting

confidence: 60%

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

Napoli¹,

Wong²,

Hertz‐Picciotto

et al. 2014

Pediatrics

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103

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“…Toxicity could occur at the subcellular level via mitochondrial dysfunction and oxidative stress, which have been reported in FXTAS. 22,23 The DTI component of this study disclosed reduced FA in premutation carriers across all 3 white matter regions studied (table e-1), and correlations of these reductions with cognitive dysfunction (table 2). However, some correlations between FA and cognition were also found in noncarrier controls (table 2), a result that may be consistent with previous findings that both FA and volume decrease in white matter with normal aging, [24][25][26] and are associated with a concomitant decline in executive function.…”

Section: Figure 2 Mrs Voxel Placementmentioning

confidence: 65%

White matter disease and cognitive impairment in FMR1 premutation carriers

Filley¹,

Brown²,

Onderko³

et al. 2015

Neurology

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Objective: This cross-sectional, observational study examined the role of white matter involvement in the cognitive impairment of individuals with the fragile X mental retardation 1 (FMR1) premutation.Methods: Eight asymptomatic premutation carriers, 5 participants with fragile X tremor/ataxia syndrome (FXTAS), and 7 noncarrier controls were studied. The mean age of the asymptomatic premutation carriers, participants with FXTAS, and noncarrier controls was 60, 71, and 67 years, respectively. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) were used to examine the middle cerebellar peduncles (MCP) and the genu and splenium of the corpus callosum in relation to executive function and processing speed. MRS measures were N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine, and fractional anisotropy (FA) was used for DTI. Executive function was assessed with the Behavioral Dyscontrol Scale and the Controlled Oral Word Association Test (COWAT), and processing speed with the Symbol Digit Modalities Test.Results: Among all 13 FMR1 premutation carriers, significant correlations were found between N-acetyl aspartate/creatine and choline/creatine in the MCP and COWAT scores, and between FA in the genu and performance on the Behavioral Dyscontrol Scale, COWAT, and Symbol Digit Modalities Test; a correlation was also found between FA in the splenium and COWAT performance. In all regions studied, participants with FXTAS had the lowest mean FA. Conclusion:Microstructural white matter disease as determined by MRS and DTI correlated with executive dysfunction and slowed processing speed in these FMR1 premutation carriers. Neuroimaging abnormalities in the genu and MCP suggest that disruption of white matter within frontocerebellar networks has an important role in the cognitive impairment associated with the FMR1 premutation. Neurology ® 2015;84:2146-2152 GLOSSARY CC 5 corpus callosum; Ch/Cr 5 choline/creatine; COWAT 5 Controlled Oral Word Association Test; DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; FMR1 5 fragile X mental retardation 1; FXS 5 fragile X syndrome; FXTAS 5 fragile X tremor/ataxia syndrome; MCP 5 middle cerebellar peduncle; MRS 5 magnetic resonance spectroscopy; NAA/Cr 5 N-acetyl aspartate/creatine; ROI 5 region of interest; TE 5 echo time; TR 5 repetition time; SDMT 5 Symbol Digit Modalities Test.Fragile X tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disease in which dementia often accompanies motor and other clinical manifestations.1 Although FXTAS can develop in women, the disease is more penetrant and severe in men.1 FXTAS is caused by a CGG repeat expansion in the premutation range (55-200) of the fragile X mental retardation 1 (FMR1) gene, in contrast to the fragile X syndrome (FXS), which is caused by .200 CGG repeats.1 Each disease has unique molecular pathogenetic features, with FXS related to transcriptional silencing with reduced or absent FMR1 protein, and FXTAS characterized by increased FMR1 messenger RNA, 1 which is thought t...

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“…60 This is relevant in the central nervous system, given that the oxidative stress threshold required for the p53-induced pro-oxidant effects in neurons is lower than those reported in any other cell type. 61 Taken together, instability in the p53 genomic region (haploinsufficiency, or altered CN) might set a background of heightened susceptibility for other detrimental triggers (environmental exposures, 33, 62 use of maternal medications and/or metabolic status, 63,64 other diseases [65][66][67][68] ) influencing the progeny outcome, especially during highly susceptible periods of development, such as perinatal stages.…”

Section: Discussionmentioning

confidence: 99%

Role ofp53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study

Wong¹,

Napoli²,

Krakowiak³

et al. 2016

Pediatrics

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The tumor suppressor p53 responds to a variety of environmental stressors by regulating cell cycle arrest, apoptosis, senescence, DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance. Developmental abnormalities have been reported in p53-deficient mice, and altered p53 and p53-associated pathways in autism (AU). Furthermore, via the Pten-p53 crosstalk, Pten haploinsufficient-mice have autisticlike behavior accompanied by brain mitochondrial dysfunction with accumulation of mtDNA deletions.

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Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome

Cited by 100 publications

References 109 publications

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

White matter disease and cognitive impairment in FMR1 premutation carriers

Role ofp53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study

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