Genetic and epigenetic study of ALS-discordant identical twins with double mutations in<i>SOD1</i>and<i>ARHGEF28</i>

Zhang, Ming; Xi, Zhengrui; Ghani, Mahdi; Jia, Pengxiang; Pal, Mrinal; Werynska, Karolina; Moreno, Danielle; Sato, Christine; Liang, Yan; Robertson, Janice; Petronis, Artūras; Zinman, Lorne; Rogaeva, Ekaterina

doi:10.1136/jnnp-2016-313592

Cited by 37 publications

(38 citation statements)

References 6 publications

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“…The finding of increased ‘epigenetic age’ in the white blood cells of all our four classic ALS patients supports the suggestion of a previous study of one ALS-discordant twin pair [ 42 ] that increased tissue aging may be a common feature in ALS. The changes to white blood cell methylation in a neurodegenerative disease such as ALS is consistent with recent findings that ALS is not a disorder of motor neurons alone, since other CNS cells such as astrocytes, oligodendrocytes, microglia, and interneurons, as well as skeletal muscle, are now implicated in its pathogenesis [ 43 ].…”

Section: Discussionsupporting

confidence: 91%

Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis

et al. 2017

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Amyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS, four with classic ALS and one with the progressive muscular atrophy ALS variant, in whom previous whole genome sequencing failed to uncover a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of differences were mostly idiosyncratic to a twin pair, a proportion involving GABA signalling were common to all ALS individuals. For both idiosyncratic and common sites the differences occurred within genes and pathways related to neurobiological functions or dysfunctions, some of particular relevance to ALS such as glutamate metabolism and the Golgi apparatus. All four classic ALS patients were epigenetically older than their unaffected co-twins, suggesting accelerated aging in multiple tissues in this disease. In conclusion, widespread changes in methylation patterns were found in ALS-affected co-twins, consistent with an epigenetic contribution to disease. These DNA methylation findings could be used to develop blood-based ALS biomarkers, gain insights into disease pathogenesis, and provide a reference for future large-scale ALS epigenetic studies.

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Section: Discussionsupporting

confidence: 91%

Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis

et al. 2017

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“…Indeed, only the affected twin had a prominent history of smoking and head injury [34], which may influence DNA methylation [17]. Notably, the difference in DNAm age suggested that the affected twin had aged faster than the asymptomatic twin; and a similar trend was detected in another pair of MZ twins carrying the SOD1 and ARHGEF28 mutations, who were ALS-discordant for 17 years [38]. …”

Section: Introductionmentioning

confidence: 99%

DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients

et al. 2017

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The repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. C9orf72 patients present with a wide range in disease duration and age of onset. The strongest risk factor for both syndromes is aging, which was linked to DNA methylation (DNAm) age based on the cumulative assessment of the methylation levels of 353 CpGs included on the genome-wide 450k BeadChip. DNAm age may reflect biological age better than chronological age. We conducted a genome-wide blood DNA methylation study of 46 unrelated C9orf72 patients. After correction for multiple testing, none of the CpGs demonstrated association between its methylation level and disease duration or age of onset. However, we detected a significant reverse correlation of DNAm age-acceleration with disease duration and age of onset, suggesting that for every 5-year increase in DNAm age-acceleration there is a 3.2-year earlier age of onset and 1.5-year shorter disease duration. The significant correlations remain after adjusting for gender, TMEM106B genotypes, disease phenotype and C9orf72 5′CpG island methylation status. A similar trend was observed for the blood DNA of affected members of an extended C9orf72 family; and tissues from the central nervous system of C9orf72 autopsy cases. For instance, regression analysis suggested that a 5-year increase in DNAm age-acceleration is linked to an earlier age of onset by 4.7 or 5.5 years for frontal cortex or spinal cord, respectively. Blood DNAm age may be a useful biomarker for biological age, because blood DNAm age-acceleration was similar to all investigated brain tissues, except for cerebellum that ages more slowly. In conclusion, DNA methylation analysis of C9orf72 patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1713-y) contains supplementary material, which is available to authorized users.

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“…Epigenetic modifications, especially DNA methylation, have been reported to be associated with aging [31], [32], AD [33], and Parkinson’s disease [34]. Furthermore, genetic variations that modulate DNA methylation age may control biological aging [35], which is the strongest risk factor for AD.…”

Section: Discussionmentioning

confidence: 99%

Drug Repositioning for Alzheimer’s Disease Based on Systematic ‘omics’ Data Mining

et al. 2016

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Traditional drug development for Alzheimer’s disease (AD) is costly, time consuming and burdened by a very low success rate. An alternative strategy is drug repositioning, redirecting existing drugs for another disease. The large amount of biological data accumulated to date warrants a comprehensive investigation to better understand AD pathogenesis and facilitate the process of anti-AD drug repositioning. Hence, we generated a list of anti-AD protein targets by analyzing the most recent publically available ‘omics’ data, including genomics, epigenomics, proteomics and metabolomics data. The information related to AD pathogenesis was obtained from the OMIM and PubMed databases. Drug-target data was extracted from the DrugBank and Therapeutic Target Database. We generated a list of 524 AD-related proteins, 18 of which are targets for 75 existing drugs—novel candidates for repurposing as anti-AD treatments. We developed a ranking algorithm to prioritize the anti-AD targets, which revealed CD33 and MIF as the strongest candidates with seven existing drugs. We also found 7 drugs inhibiting a known anti-AD target (acetylcholinesterase) that may be repurposed for treating the cognitive symptoms of AD. The CAD protein and 8 proteins implicated by two ‘omics’ approaches (ABCA7, APOE, BIN1, PICALM, CELF1, INPP5D, SPON1, and SOD3) might also be promising targets for anti-AD drug development. Our systematic ‘omics’ mining suggested drugs with novel anti-AD indications, including drugs modulating the immune system or reducing neuroinflammation that are particularly promising for AD intervention. Furthermore, the list of 524 AD-related proteins could be useful not only as potential anti-AD targets but also considered for AD biomarker development.

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Genetic and epigenetic study of ALS-discordant identical twins with double mutations inSOD1andARHGEF28

Cited by 37 publications

References 6 publications

Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis

Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis

DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients

Drug Repositioning for Alzheimer’s Disease Based on Systematic ‘omics’ Data Mining

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