A Study of Potential Interactive Genetic Factors in Huntington’s Disease

Panegyres, Peter K.; Beilby, John; Bulsara, Max; Zafiris-Toufexis, K.; Wong, Cathy M.

doi:10.1159/000093867

Cited by 17 publications

(12 citation statements)

References 58 publications

(33 reference statements)

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“…Specifically, APOE had been linked to Parkinson disease (PD) (149,150), chronic traumatic encephalopathy (151), Huntington disease (152,153), frontotemporal dementia (FTD) (154), and certain subsets of amyotrophic lateral sclerosis (155)(156)(157), though the latter findings conflicted with some other studies (158)(159)(160). Here, we discuss the current state of knowledge on the specific interaction between APOE and the aggregation-prone proteins associated with some of these diseases.…”

Section: Apoe and Other Amyloidogenic Proteinsmentioning

confidence: 95%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

180

145

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In 1907, the German psychiatrist, Alois Alzheimer, published a case report, "On an unusual illness of the cerebral cortex," in which he described what we now know as Alzheimer's disease (AD) (1). More than a century after this landmark discovery, AD is now recognized as the most common cause of late-life dementia. AD pathology is characterized by the cerebral accumulation of amyloid plaques and neurofibrillary tangles, both of which consist predominantly of specific insoluble protein aggregates. The majority of AD cases are sporadic and have a relatively late onset, predominantly after the age of 65. This form of AD is known as late-onset AD (LOAD), in contrast to early-onset AD, which has a strong genetic component, is often autosomal dominant, and accounts for less than 1% of AD cases (2). While most genetic risk factors for LOAD identified in the past two decades have a relatively small impact on AD risk, extensive epidemiological, clinical, and pathological studies have established the APOE gene on chromosome 19 as the most important genetic risk factor for developing LOAD (3-5). This locus encodes a 299 amino acid glycoprotein (apoE) that is expressed in several cell types, with highest expression levels found in the liver and the brain, where it is expressed predominantly by astrocytes (6) and, to a lesser extent, microglia (7,8). The human APOE gene Abstract Alzheimer's disease (AD) is one of the fastestgrowing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified APOE as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid- (A). Here, we discuss the role of apoE on the biophysical properties and metabolism of the A peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including A) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond A, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.

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Section: Apoe and Other Amyloidogenic Proteinsmentioning

confidence: 95%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

180

145

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“…15,24 The potential correlation between the polymorphic CCG region and the age of onset of the disease is controversial. According to Panegyres et al, 25 who studied an Australian population, the CCG region does not correlate with the age of onset of HD, the neurological symptoms or the number of CAG repeats. On the other hand, Chattopadhyay et al 26 found that, in an Indian population, variation in the length of the CCG region was responsible for 3.1% of variation in the age of onset of the disease.…”

Section: Discussionmentioning

confidence: 96%

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

et al. 2012

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We studied the allelic profile of CAG and CCG repeats in 61 Brazilian individuals in 21 independent families affected by Huntington's disease (HD). Thirteen individuals had two normal alleles for HD, two had one mutable normal allele and no HD phenotype, and forty-six patients carried at least one expanded CAG repeat allele. Forty-five of these individuals had one expanded allele and one individual had one mutable normal allele (27 CAG repeats) and one expanded allele (48 CAG repeats). Eleven of these forty-five subjects had a mutant allele with reduced penetrance, and thirty-four patients had a mutant allele with complete penetrance. Inter-and intragenerational investigations of CAG repeats were also performed. We found a negative correlation between the number of CAG repeats and the age of disease onset (r ¼ À0.84; Po0.001) and no correlation between the number of CCG repeats and the age of disease onset (r ¼ 0.06). We found 40 different haplotypes and the analysis showed that (CCG) 10 was linked to a CAG normal allele in 19 haplotypes and to expanded alleles in two haplotypes. We found that (CCG) 7 was linked to expanded CAG repeats in 40 haplotypes (95.24%) and (CCG) 10 was linked to expanded CAG repeats in only two haplotypes (4.76%). Therefore, (CCG) 7 was the most common allele in HD chromosomes in this Brazilian sample. It was also observed that there was a significant association of (CCG) 7 with the expanded CAG alleles (v 2 ¼ 6.97, P ¼ 0.0084). Worldwide, the most common CCG alleles have 7 or 10 repeats. In Western Europe, (CCG) 7 is the most frequent allele, similarly to our findings.

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“…It is well known that the HD expansion is overrepresented on a subset of the haplotypes associated with non-disease-associated alleles. Notably, a potential methylationmodifying polymorphism exists in the form of the polymorphic CCG repeat, which lies immediately downstream of the CAG repeat 21 and tags many of the most common HTT haplotypes. We evaluated five multivariate linear regression models to examine if the association between HTT cg22982173 and CAG length could possibly arise as an artifact of linkage disequilibrium between the CAG repeat and some other methylation-modifying variants at the HTT locus ("Methods").…”

Section: Resultsmentioning

confidence: 99%

DNA methylation study of Huntington’s disease and motor progression in patients and in animal models

Narayan

Grant

et al. 2020

Nat Commun

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Although Huntington’s disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10−7) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10−26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10−8) and in the transgenic sheep model (p = 2.4 × 10−88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10−7) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10−9), GRIK4 (p = 3.0 × 10−8), and COX4I2 (p = 6.5 × 10−8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.

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A Study of Potential Interactive Genetic Factors in Huntington’s Disease

Cited by 17 publications

References 58 publications

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

DNA methylation study of Huntington’s disease and motor progression in patients and in animal models

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