Zinc is recognized as an essential trace metal required for human health; its deficiency is strongly associated with neuronal and immune system defects. Although zinc is a redox-inert metal, it functions as an antioxidant through the catalytic action of copper/zinc-superoxide dismutase, stabilization of membrane structure, protection of the protein sulfhydryl groups, and upregulation of the expression of metallothionein, which possesses a metal-binding capacity and also exhibits antioxidant functions. In addition, zinc suppresses anti-inflammatory responses that would otherwise augment oxidative stress. The actions of zinc are not straightforward owing to its numerous roles in biological systems. It has been shown that zinc deficiency and zinc excess cause cellular oxidative stress. To gain insights into the dual action of zinc, as either an antioxidant or a prooxidant, and the conditions under which each role is performed, the oxidative stresses that occur in zinc deficiency and zinc overload in conjunction with the intracellular regulation of free zinc are summarized. Additionally, the regulatory role of zinc in mitochondrial homeostasis and its impact on oxidative stress are briefly addressed.

/pdf/critical-role-of-zinc-as-either-an-antioxidant-or-a-1m55b3qjl8.pdf

Critical Role of Zinc as Either an Antioxidant or a Prooxidant in Cellular Systems.

Summary Fragile X syndrome, the most common heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X ( FMR1 ) gene owing to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, so-called premutation expansions (55–200 repeats) can cause a family of neurodevelopmental phenotypes (attention deficit hyperactivity disorder, autism spectrum disorder, seizure disorder) and neurodegenerative (fragile X-associated tremor/ataxia syndrome [FXTAS]) phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Results of basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the range of clinical manifestations. Advances of knowledge on both mechanistic and clinical fronts are driving new approaches to targeted treatment, but two important necessities are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features.

/pdf/advances-in-clinical-and-molecular-understanding-of-the-fmr1-4eucse95cc.pdf

Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (> 200 repeats) in the 5' untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and γ aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.

/pdf/fragile-x-and-autism-intertwined-at-the-molecular-level-2pdbs0q2pv.pdf

Fragile X and autism : intertwined at the molecular level leading to targeted treatments

Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers.

Fragile X-associated tremor/ataxia syndrome - features, mechanisms and management.

The human fragile X mental retardation 1 (FMR1) gene contains a (CGG)n trinucleotide repeat that is responsible for a number of heritable disorders affecting both early neurodevelopment and late-onset neurodegeneration (Willemsen et al. 2011; Leehey and Hagerman 2012). The repeat element is located in the 5′ untranslated region (5′UTR) of the gene and is thus transcribed into mRNA but not translated into the FMR1 protein product (FMRP). Expanded alleles in the premutation range (55–200 CGG repeats) result in elevated FMR1 mRNA expression (Tassone et al. 2000) and are associated with a number of disorders including the adult-onset neurodegenerative disorder, fragile X–associated tremor/ataxia syndrome (FXTAS) (Leehey and Hagerman 2012), fragile X–associated premature ovarian insufficiency (FXPOI) (Wittenberger et al. 2007; Sullivan et al. 2011), as well as learning disabilities, autism spectrum disorders, ADHD, and seizures (Farzin et al. 2006; Clifford et al. 2007; Chonchaiya et al. 2012). The molecular pathology of premutation expansion disorders is generally considered to be a toxic RNA gain of function resulting from the expanded CGG-repeat region in the mRNA (Garcia-Arocena and Hagerman 2010; Ross-Inta et al. 2010; Sellier et al. 2010). Alleles in this range also show a propensity to expand beyond 200 repeats (full mutation range) upon maternal transmission, in which case the FMR1 CpG-island promoter generally becomes hypermethylated and transcriptionally silenced (Willemsen et al. 2011). The resultant loss of FMRP expression disrupts early neurodevelopment and leads to fragile X syndrome (FXS), the most common heritable form of cognitive impairment and the most common single-gene mutation associated with autism (Willemsen et al. 2011; Hagerman et al. 2012).

CGG-repeat expansions have been the focus of intense research since identification of the gene in 1991 (Verkerk et al. 1991); however, the inability to sequence repeat-expansion alleles in the disease-relevant size range has limited their complete genetic and epigenetic characterization. Indeed, investigators of the original gene-discovery study noted their inability to sequence the CGG repeats, and other early attempts to use sequencing to characterize the repeats describe the inability to fully traverse the region (Hornstra et al. 1993). Whereas PCR and Southern blotting are capable of genotyping repeat expansion alleles on the basis of DNA fragment size (Nolin et al. 2003; Saluto et al. 2005; Filipovic-Sadic et al. 2010), and even identify methylation status and AGG-repeat interruptions (Chen et al. 2010, 2011; Yrigollen et al. 2012), such methods lack the single-nucleotide resolution obtained with DNA sequencing and, more importantly, are severely limited in their ability to detect the presence of minor alleles. Furthermore, because dideoxyribose sequencing strategies (Sanger et al. 1977) and most “next-generation” sequencing technologies (Metzker 2010) rely on reading signal from bulk DNA populations, they are limited by the loss of sequence phase coherence—a particular problem for GC-rich sequence—as well as decreasing size resolution with increasing DNA length. As a consequence, it is generally not possible to sequence FMR1 alleles in excess of ∼100 CGG repeats, a limit that falls well short of the full mutation range that is responsible for fragile X syndrome.

A fundamentally different sequencing approach, single-molecule, real-time (SMRT) sequencing, uses zero-mode waveguide (ZMW) nanowells to determine DNA sequence from individual DNA templates (Fig. 1; Eid et al. 2009). This is accomplished through real-time observation of individual nucleotide incorporation events catalyzed by a single DNA polymerase. This approach bypasses critical limitations of previous technologies in the context of highly repetitive sequences such as trinucleotide expansions. In particular, measurement of the signal from isolated molecules overcomes the problems of sample heterogeneity (phase-coherence) and diminishing resolution inherent in bulk sequencing approaches. Since the SMRT sequencing reads are limited only by loss of activity of individual polymerase molecules, single-molecule readlengths approaching 15 kb (average readlengths approaching 3 kb) (Rasko et al. 2011; Sebra et al. 2012) can be attained, with improved sequence accuracy achieved by iteratively sequencing the same SMRTbell circular sequencing template (circular consensus sequencing [CCS]) (Fig. 1; Travers et al. 2010).



Figure 1.

Schematic representation of SMRT sequencing. DNA polymerase synthesizes a nascent strand complementary to a closed-circular SMRTbell DNA template. Fluorescent phospholinked nucleotides produce real-time fluorescent pulse data for both basecalls and incorporation ...



By utilizing the SMRT sequencing approach for the analysis of the CGG-repeat region of the FMR1 gene, we have demonstrated that it is possible to generate sequence data for FMR1 alleles in excess of 750 CGG repeats, which translates to over 2.25 kb of 100% CGG-repeat DNA. We show that this method produces repeat-size distributions reflective of the distributions expected from the input (e.g., cloned or PCR-amplified) DNA. We also demonstrate that by using CCS reads, we are able to identify AGG “interruptions” within the CGG-repeat tract that are of direct medical relevance (Yrigollen et al. 2012). Our approach should be broadly applicable to the analysis of other repetitive elements, particularly those containing high CG content and possessing short homopolymer runs (e.g., the GGGGCC motif in 9p-linked amyotrophic lateral sclerosis-frontal temporal dementia [ALS-FTLD]) (DeJesus-Hernandez et al. 2011; Renton et al. 2011). Finally, SMRT sequencing possesses the unique capability of analyzing the kinetics of individual DNA polymerase molecules, and we show clear, strand-specific transitions within the CGG-repeat region, which should facilitate future studies of differential methylation.

/pdf/sequencing-the-unsequenceable-expanded-cgg-repeat-alleles-of-30g5lckkye.pdf

Sequencing the unsequenceable: Expanded CGG-repeat alleles of the fragile X gene

FXTAS (fragile X-associated tremor/ataxia syndrome) is a late-onset neurodegenerative disorder that affects individuals who are carriers of premutation expansions (55-200 CGG repeats) in the 5' untranslated region of the FMR1 (fragile X mental retardation 1) gene. The role of MD (mitochondrial dysfunction) in FXTAS was evaluated in fibroblasts and brain samples from premutation carriers with and without FXTAS symptoms, with a range of CGG repeats. This study resulted in several important conclusions: (i) decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers; (ii) a lower expression of mitochondrial proteins preceded both in age and in CGG repeats the appearance of overt clinical involvement; (iii) the CGG repeat size required for altered mitochondrial protein expression was also smaller than that required to produce brain intranuclear inclusions from individuals with the premutation who died, suggesting that MD is an incipient pathological process occurring in individuals who do not display overt features of FXTAS; and (iv) on the basis of the CGG repeats, MD preceded the increase in oxidative/nitrative stress damage, indicating that the latter is a late event. MD in carriers of small CGG repeats, even when the allele size is not sufficient to produce FXTAS, may predispose them to other disorders (e.g. Parkinson's disease) that are likely to involve MD, and to environmental stressors, which may trigger the development of FXTAS symptoms. Detection of MD is of critical importance to the management of FXTAS, since it opens up additional treatment options for this disorder.

/pdf/evidence-of-mitochondrial-dysfunction-in-fragile-x-14dwwko9uz.pdf

Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects individuals who are carriers of small CGG premutation expansions in the fragile X mental retardation 1 (FMR1) gene. Mitochondrial dysfunction was observed as an incipient pathological process occurring in individuals who do not display overt features of FXTAS ( 1). Fibroblasts from premutation carriers had lower oxidative phosphorylation capacity (35% of controls) and Complex IV activity (45%), and higher precursor-to-mature ratios (P:M) of nDNA-encoded mitochondrial proteins (3.1-fold). However, fibroblasts from carriers with FXTAS symptoms presented higher FMR1 mRNA expression (3-fold) and lower Complex V (38%) and aconitase activities (43%). Higher P:M of ATPase β-subunit (ATPB) and frataxin were also observed in cortex from patients that died with FXTAS symptoms. Biochemical findings observed in FXTAS cells (lower mature frataxin, lower Complex IV and aconitase activities) along with common phenotypic traits shared by Friedreich's ataxia and FXTAS carriers (e.g. gait ataxia, loss of coordination) are consistent with a defective iron homeostasis in both diseases. Higher P:M, and lower ZnT6 and mature frataxin protein expression suggested defective zinc and iron metabolism arising from altered ZnT protein expression, which in turn impairs the activity of mitochondrial Zn-dependent proteases, critical for the import and processing of cytosolic precursors, such as frataxin. In support of this hypothesis, Zn-treated fibroblasts showed a significant recovery of ATPB P:M, ATPase activity and doubling time, whereas Zn and desferrioxamine extended these recoveries and rescued Complex IV activity.

/pdf/altered-zinc-transport-disrupts-mitochondrial-protein-3yd2wnfz19.pdf

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

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Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

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