Autopsy study of cerebellar degeneration in siblings with ataxia-telangiectasia-like disorder

Oba, Daiju; Hayashi, Masaharu; Minamitani, Motoyuki; Hamano, Shin‐ichiro; Uchisaka, Naoki; Kikuchi, Akira; Kishimoto, Hiroshi; Takagi, Motoki; Morio, Tomohiro; Mizutani, Shuki

doi:10.1007/s00401-010-0639-4

Cited by 26 publications

(16 citation statements)

References 28 publications

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“…The involvement of the thalamus has also been reported previously in patients with spinocerebellar ataxias type 2, 3 and 7 [90], [91], [92] and [93], autosomal recessive ataxia [94] and patients with Wernicke-Korsakoff syndrome [89]. In addition, loss of granule cells in the cerebellum has been previously reported in siblings with ataxia-telangiectasia-like disorder [95] as well as in mouse models of ataxia [84], [82] and [83]. Although the relationship between Cplx1 and ataxia is not known [2] and [11], the high levels of Cplx1 expression in the cerebellum and thalamus [14], the reduced volume of these regions in Cplx1 −/− mice reported here and the involvement of the cerebellum and thalamus in movement control seem to indicate that both these regions might be involved in the development of the abnormal motor function that is a result of Cplx1 depletion in mice.…”

Section: Discussionsupporting

confidence: 57%

Tensor-Based Morphometry and Stereology Reveal Brain Pathology in the Complexin1 Knockout Mouse

et al. 2012

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Complexins (Cplxs) are small, soluble, regulatory proteins that bind reversibly to the SNARE complex and modulate synaptic vesicle release. Cplx1 knockout mice (Cplx1−/−) have the earliest known onset of ataxia seen in a mouse model, although hitherto no histopathology has been described in these mice. Nevertheless, the profound neurological phenotype displayed by Cplx1−/− mutants suggests that significant functional abnormalities must be present in these animals. In this study, MRI was used to automatically detect regions where structural differences were not obvious when using a traditional histological approach. Tensor-based morphometry of Cplx1−/− mouse brains showed selective volume loss from the thalamus and cerebellum. Stereological analysis of Cplx1−/− and Cplx1+/+ mice brain slices confirmed the volume loss in the thalamus as well as loss in some lobules of the cerebellum. Finally, stereology was used to show that there was loss of cerebellar granule cells in Cplx1−/− mice when compared to Cplx1+/+ animals. Our study is the first to describe pathological changes in Cplx1−/− mouse brain. We suggest that the ataxia in Cplx1−/− mice is likely to be due to pathological changes in both cerebellum and thalamus. Reduced levels of Cplx proteins have been reported in brains of patients with neurodegenerative diseases. Therefore, understanding the effects of Cplx depletion in brains from Cplx1−/− mice may also shed light on the mechanisms underlying pathophysiology in disorders in which loss of Cplx1 occurs.

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Section: Discussionsupporting

confidence: 57%

Tensor-Based Morphometry and Stereology Reveal Brain Pathology in the Complexin1 Knockout Mouse

et al. 2012

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“…Complete loss of function is embryonic lethal (Friedberg and Meira, 2006; Xiao and Weaver, 1997). A neuropathological study of a pair of male siblings with the same heterozygous mutations of the MRE11 gene found both cerebellar atrophy and the absence of MRE11 in the neurons of the cerebellar cortex, cerebral cortex, basal ganglia and midbrain (Oba et al, 2010). Cerebellar atrophy in the two siblings was already present at infancy as indicated by magnetic resonance imaging studies.…”

Section: Double-strand Break Repair Deficiencymentioning

confidence: 99%

DNA repair deficiency in neurodegeneration

Jeppesen

Bohr

Stevnsner

2011

Progress in Neurobiology

301

268

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Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington’s disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.

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“…Symptoms of A-T include altered DNA damage repair, immunodeficiency, increased cancer incidence, sterility, and muscle atrophy (Barlow et al 1998;Boder and Sedgwick 1958;Chun and Gatti 2004;Eisen et al 1965;Gotoff et al 1967;Kwast and Ignatowicz 1990). Although cerebellar atrophy is most prominent, patients exhibit degenerative changes of various severities in various brain regions (Habek et al 2008;Oba et al 2010;Tavani et al 2003;Verhagen et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Mutation of ataxia–telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia

Campbell

Bushman

Munger

et al. 2015

Glia

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Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia–telangiectasia (A–T), a disease caused by mutations in the ataxia–telangiectasia mutated (ATM) gene. A hallmark of A–T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A–T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A–T astroglia. Metabolic labeling of L-cystine, the major precursor for GSH, revealed that a key component of the defect in A–T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A–T mutant astroglia providing a possible future avenue for targeted therapeutic intervention.

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Autopsy study of cerebellar degeneration in siblings with ataxia-telangiectasia-like disorder

Cited by 26 publications

References 28 publications

Tensor-Based Morphometry and Stereology Reveal Brain Pathology in the Complexin1 Knockout Mouse

Tensor-Based Morphometry and Stereology Reveal Brain Pathology in the Complexin1 Knockout Mouse

DNA repair deficiency in neurodegeneration

Mutation of ataxia–telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia

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