Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients

Belzil, Véronique V.; Bauer, Peter; Gendron, Tania F.; Murray, Melissa E.; Dickson, Dennis W.; Petrucelli, Leonard

doi:10.1016/j.brainres.2014.02.015

Cited by 75 publications

(69 citation statements)

References 19 publications

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“…39 Alternatively, or in combination, epigenetic modifications, such as hypermethylation of CpG islands juxtaposing the repeats or binding of trimethylated histones, may underlie decreased abundance of C9orf72 transcripts. 24,31,[38][39][40] At the immunohistochemical level, C9-L antibody showed a diffuse labeling in the cytoplasm of cerebellar Purkinje cells, with a striking labeling of numerous speckles that were observed both in the neuronal perikarya and dendritic processes. The identity of these speckles remains unknown, and it should be noted that they were observed in both c9-ALS and non-c9-ALS cases.…”

Section: Figurementioning

confidence: 99%

“…In contrast, C9-S antibody gave a very specific labeling of the nuclear membrane, clearly showing that C9-L and C9-S have different subcellular localizations in Purkinje cells. Previously published reports using commercial antibodies against C9orf72 protein have noted diffuse and granular staining in neuronal cytoplasm and neurites; however, these antibodies show high levels of nonspecific staining and are either unable to discriminate between C9-L and C9-S or are solely directed against C9-L. 11,12,15,16,40,44 Thus, our antibodies provide greatly improved detection of C9orf72 protein isoforms and have revealed distinct subcellular localizations of C9-L and C9-S. Immunohistochemical labeling of spinal cord tissue showed that the subcellular localization of C9-L in diseased motor neurons appeared unchanged in c9-ALS and non-c9-ALS cases compared to controls. However, changes in the relative intensity of staining between cases were apparent, with some c9-ALS cases showing a relative increase in labeling and others a decrease.…”

Section: Figurementioning

confidence: 99%

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Isoform‐specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis

Xiao

MacNair

McGoldrick

et al. 2015

Annals of Neurology

122

193

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Objective: A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It has been reported that the repeat expansion causes a downregulation of C9orf72 transcripts, suggesting that haploinsufficiency may contribute to disease pathogenesis. Two protein isoforms are generated from three alternatively spliced transcripts of C9orf72; a long form (C9-L) and a short form (C9-S), and their function(s) are largely unknown owing to lack of specific antibodies. Methods: To investigate C9orf72 protein properties, we developed novel antibodies that recognize either C9-L or C9-S. Multiple techniques, including Western blot, immunohistochemistry, and coimmunoprecipitation, were used to determine the expression levels and subcellular localizations of C9-L and C9-S. Results: Investigation of expression of C9-L and C9-S demonstrated distinct biochemical profiles, region-specific changes, and distinct subcellular localizations in ALS tissues. In particular, C9-L antibody exhibited a diffuse cytoplasmic staining in neurons and labeled large speckles in cerebellar Purkinje cells. In contrast, C9-S antibody gave very specific labeling of the nuclear membrane in healthy neurons, with apparent relocalization to the plasma membrane of diseased motor neurons in ALS. Coimmunoprecipitation experiments revealed an interaction of the C9-isoforms with both Importin b1 and Ran-GTPase, components of the nuclear pore complex. Interpretation: Using these antibodies, we have shown that C9orf72 may be involved in nucleocytoplasmic shuttling and this may have relevance to pathophysiology of ALS/FTLD. Our antibodies have provided improved detection of C9orf72 protein isoforms, which will help elucidate its physiological function and role in ALS/FTLD. ANN NEUROL 2015;78:568-583 H exanucleotide (G 4 C 2 ) repeat expansions within a noncoding region of C9orf72 are the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), accounting for up to 50% of ALS, 29% of FTLD, and 88% of ALS/ FTLD patients, including familial and sporadic cases.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Isoform‐specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis

Xiao

MacNair

McGoldrick

et al. 2015

Annals of Neurology

122

193

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“…Возросший интерес к этой области науки при БАС и ЛВД связан с возможностью иссле-дования новых теорий развития заболевания, что мо-жет обеспечить понимание механизмов этих 2 леталь-ных патологий. Существуют противоречивые данные о том, что эпигенетическая модификация гена C9orf72 посредством гиперметилирования значимо коррели-рует с более быстрым течением заболевания, однако в других исследованиях показан нейропротективный эффект для этой категории пациентов [14][15][16][17]. Гипер-метилирование CpG-островков 5' -промоторной области гена C9orf72 продемонстрировано различными группами исследователей и встречается примерно в 10-30 % случаев среди пациентов с экспансией в ге-не C9orf72 [14,17], вероятно, приводя к снижению уровня экспрессии C9orf72.…”

Section: оригинальные исследованияunclassified

“…Метилирование этой об-ласти обнаружено только у 2 сибсов в группе носите-лей полной экспансии. Таким образом, частота встре-чаемости мутации в нашей когорте составила 9,1 % (1 / 11), что согласуется с результатами других исследо-ваний (10-30 %) [14,17]. Присутствие сходных сайтов метилирования у обоих пациентов-родственников может говорить о наследуемости данной модификации гена.…”

Section: том 8 Volunclassified

“…Изменение клинического фенотипа у нашего пациента может быть результатом снижения уровня экспрессии патологического аллеля вследствие метилирования 5' -промоторной области гена C9orf72, что может способствовать уменьшению токсического эффекта экспансии. По данным других исследований, четкой корреляции статуса метилирова-ния с фенотипическим вариантом нейродегенератив-ного процесса либо продолжительностью заболевания не выявлено [14][15][16][17]. Для поиска и анализа более де-тальных клинико-эпигенетических корреляций необ-ходимы дальнейшие исследования на большей когорте пациентов с БАС и другой C9orf72-ассоциированной нейродегенеративной патологией.…”

Section: том 8 Volunclassified

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Evaluation of methylation status of the 5’-promoter region of C9orf72 gene in Russian patients with neurodegenerative diseases

Шпилюкова¹,

Федотова²,

Pogoda³

et al. 2018

Neuromuscular Diseases

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Background. Hexanucleotide repeat expansion in the C9orf72 gene is the most significant cause of a large number of neurodegenerative diseases: frontotemporal degeneration (FTD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), etc. Several studies have shown the relationship with the neurodegenerative process for full (>40 GGGGCC copies) and intermediate (13–20) repeats expansion. Methylation of the C9orf72 gene can play an important role in the pathogenesis of FTD and ALS, but the mechanism has not been sufficiently studied.The objective is to investigate the status of methylation of the 5’-promotor region of the C9orf72 gene in patients with neurodegenerative disorders having full or intermediate expansion of GGGGCC-repeats.Materials and methods. We investigated the methylation status of the 5’-promoter region of full C9orf72 expansions in FTD/ALS patients (n = 12), of intermediate expansions in Parkinson’s disease patients (n = 8) and of non-expanded alleles in healthy controls (n = 8). Methylation status was determined via sequencing of amplified fragments of bisulfite-converted DNA.Results. We identified two cases (sibling) with the hypermethylation of the 5’-promoter region in the full C9orf72 expansions group. Patient A. (65 years old, male) had an atypical ALS presentation: an onset with head tremor, a long duration of ALS symptoms (9 years at this time), and cognitive impairments with a temporal lobes atrophy. The patient’s sister had a similar clinical phenotype. There were no cases of the promoter hypermethylation in the intermediate and control groups.Conclusion. This is the first data on the 5’-promoter region C9orf72 gene methylation in Russian population. The frequency of the promoter methylation in this group was 9.1 % that consistent with previous studies in other populations. Atypical clinical presentation may indicate a modifying effect of methylation in this area on the ALS phenotype.

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Susceptibility Genes and Epigenetics in Sporadic ALS

Morrice

Shaw

Gregory‐Evans

2021

Spectrums of Amyotrophic Lateral Sclerosis

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Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients

Cited by 75 publications

References 19 publications

Isoform‐specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis

Isoform‐specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis

Evaluation of methylation status of the 5’-promoter region of C9orf72 gene in Russian patients with neurodegenerative diseases

Susceptibility Genes and Epigenetics in Sporadic ALS

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