Huntington's disease: nearly four decades of human molecular genetics.
Ontology highlight
ABSTRACT:
SUBMITTER: Gusella JF
PROVIDER: S-EPMC8490011 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
Huntington's disease: nearly four decades of human molecular genetics.
Gusella James F JF Lee Jong-Min JM MacDonald Marcy E ME
Human molecular genetics 20211001 R2
Huntington's disease (HD) is a devastating neurogenetic disorder whose familial nature and progressive course were first described in the 19th century but for which no disease-modifying treatment is yet available. Through the active participation of HD families, this disorder has acted as a flagship for the application of human molecular genetic strategies to identify disease genes, understand pathogenesis and identify rational targets for development of therapies. ...[more]
Similar Datasets
Project description:Kelp forests are among the most abundant and productive marine ecosystems but are under threat from climate change and other anthropogenic stressors. Although knowledge is growing about how the abundance and distribution of kelp forests are changing, much less is known about the "non-lethal" effects that global change is having on the performance and health of kelp populations in areas where they persist. Here we assessed the age distribution of two common stipitate kelp species, Laminaria setchelli and Pterygophora californica, at Wizard Islet in Barkley Sound, British Columbia, Canada, and compared these data to historical demographic data collected by De Wreede (1984) and Klinger and DeWreede (1988) from the same site between 1981 and 1983. We observed that L. setchelli populations in 2020 were younger and less evenly aged than the same populations sampled nearly four decades prior, while the P. californica population was composed of older individuals on average than at the historical time point. Although the drivers of these demographic changes remain unclear, Barkley Sound has experienced substantial changes in the physical and biological environment over the past decade that could be responsible for these patterns. Given that the size of an individual and its probability of reproduction increases with age, shifting demographics may impact the reproductive output of each population, potentially altering the competitive relationships between co-occurring species. Changes in size distribution may also influence ecosystem-level processes such as habitat complexity or productivity.
| S-EPMC11914948 | biostudies-literature
Project description:BackgroundSome latrines remain unused even under conditions of high coverage in rural areas of low- and middle-income countries. Not much is known on household latrine use in the long term in the absence of an intervention. The current work assesses drivers and barriers to sustained use of a ventilated improved pit latrine (Blair VIP) design where it originated and how rural households adapt it to climate change.MethodsA mixed methods study was conducted from November 2020 to May 2021 among rural households of Mbire district, Zimbabwe. A cross sectional survey of 238 households with Blair ventilated improved pit (BVIP) latrines was conducted using a questionnaire and a latrine observation checklist. Data were analysed using logistic regression. Qualitative data were collected using six focus groups among house heads and analysed by thematic analysis.ResultThe latrine has perceived health, non-health and hygiene benefits for its sustained use. However, there are design, environmental and social barriers. The quantitative study indicated that determinants of latrine use were contextual (individual and household levels) and technology (individual level) factors. Focus groups indicated that latrine use was influenced by social, technology and contextual factors at multiple level factors. Interplay of factors influenced the intention to adapt the BVIP latrine to climate change. Local climate change adaptation strategies for the latrine were odour and erosion control, construction of the conventional latrine design and raised structures.ConclusionThe conventional BVIP latrine design is durable and relatively resilient to climate change with high local household use. High construction cost of the latrine causes households to build incomplete and poor quality designs which affect odour and fly control. These are barriers to sustained latrine use. The government should implement the new sanitation policy which considers alternative sanitation options and offer community support for adapting sanitation to climate change.
| S-EPMC8975012 | biostudies-literature
Project description:Huntington's disease (HD) is a neurodegenerative disorder caused by an expansion mutation of the cytosine-adenine-guanine (CAG) trinucleotide in the HTT gene. Decline in cognitive and motor functioning during the prodromal phase has been reported, and understanding genetic influences on prodromal disease progression beyond CAG will benefit intervention therapies. From a prodromal HD cohort (N = 715), we extracted gray matter (GM) components through independent component analysis and tested them for associations with cognitive and motor functioning that cannot be accounted for by CAG-induced disease burden (cumulative effects of CAG expansion and age). Furthermore, we examined genetic associations (at the genomic, HD pathway, and candidate region levels) with the GM components that were related to functional decline. After accounting for disease burden, GM in a component containing cuneus, lingual, and middle occipital regions was positively associated with attention and working memory performance, and the effect size was about a tenth of that of disease burden. Prodromal participants with at least one dystonia sign also had significantly lower GM volume in a bilateral inferior parietal component than participants without dystonia, after controlling for the disease burden. Two single-nucleotide polymorphisms (SNPs: rs71358386 in NCOR1 and rs71358386 in ADORA2B) in the HD pathway were significantly associated with GM volume in the cuneus component, with minor alleles being linked to reduced GM volume. Additionally, homozygous minor allele carriers of SNPs in a candidate region of ch15q13.3 had significantly higher GM volume in the inferior parietal component, and one minor allele copy was associated with a total motor score decrease of 0.14 U. Our findings depict an early genetical GM reduction in prodromal HD that occurs irrespective of disease burden and affects regions important for cognitive and motor functioning.
| S-EPMC5884935 | biostudies-literature
Project description:Although Huntington's disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest that Huntington's disease might affect neurodevelopment. To determine whether this is actually the case, we examined tissue from human fetuses (13 weeks gestation) that carried the Huntington's disease mutation. These tissues showed clear abnormalities in the developing cortex, including mislocalization of mutant huntingtin and junctional complex proteins, defects in neuroprogenitor cell polarity and differentiation, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. We observed the same phenomena in Huntington's disease mouse embryos, where we linked these abnormalities to defects in interkinetic nuclear migration of progenitor cells. Huntington's disease thus has a neurodevelopmental component and is not solely a degenerative disease.
| S-EPMC7859879 | biostudies-literature
Project description: Not available
| S-EPMC8119370 | biostudies-literature
Project description:Scientists routinely integrate information from various channels to explore topics under study. We designed a 4-wk undergraduate laboratory module that used a multifaceted approach to study a question in molecular genetics. Specifically, students investigated whether Caenorhabditis elegans can be a useful model system for studying genes associated with human disease. In a large-enrollment, sophomore-level laboratory course, groups of three to four students were assigned a gene associated with either breast cancer (brc-1), Wilson disease (cua-1), ovarian dysgenesis (fshr-1), or colon cancer (mlh-1). Students compared observable phenotypes of wild-type C. elegans and C. elegans with a homozygous deletion in the assigned gene. They confirmed the genetic deletion with nested polymerase chain reaction and performed a bioinformatics analysis to predict how the deletion would affect the encoded mRNA and protein. Students also performed RNA interference (RNAi) against their assigned gene and evaluated whether RNAi caused a phenotype similar to that of the genetic deletion. As a capstone activity, students prepared scientific posters in which they presented their data, evaluated whether C. elegans was a useful model system for studying their assigned genes, and proposed future directions. Assessment showed gains in understanding genotype versus phenotype, RNAi, common bioinformatics tools, and the utility of model organisms.
| S-EPMC3366902 | biostudies-literature
Project description:Huntington's disease (HD) is a devastating neurodegenerative disorder that is caused by an abnormal expansion of CAG repeats in the Huntingtin (HTT) gene. Although the main symptomatology is explained by alterations at the level of the central nervous system, predominantly affecting the basal ganglia, a peripheral component of the disease is being increasingly acknowledged. Therefore, the manifestation of the disease is complex and variable among CAG expansion carriers, introducing uncertainty in the appearance of specific signs, age of onset and severity of disease. The monogenic nature of the disorder allows a precise diagnosis, but the use of biomarkers with prognostic value is still needed to achieve clinical management of the patients in an individual manner. In addition, we need tools to evaluate the patient's response to potential therapeutic approaches. In this review, we provide a succinct summary of the most interesting molecular biomarkers that have been assessed in patients, mostly obtained from body fluids such as cerebrospinal fluid, peripheral blood and saliva.
| S-EPMC9142992 | biostudies-literature
Project description:BackgroundBibliometric and scientometric methods can be applied to the study of a research field.ObjectiveWe hypothesized that a bibliometric and scientometric analysis of the Alzheimer's disease (AD) research field could render trends that provide researchers and funding agencies valuable insight into the history of the field, current tendencies, and potential future directions.MethodsWe performed searches in publicly available databases including PubMed, Scopus, Web of Science, and Alzheimer's Funding Analyzer for the period 1975-2014, and conducted a curve fitting analysis with non-linear regression.ResultsWhile the rate and impact of publications continue to increase, the number of patents per year is currently declining after peaking in the late 2000s, and the funding budget has plateaued in the last 5-10 years analyzed. Genetics is the area growing at a fastest pace, whereas pathophysiology and therapy have not grown further in the last decade. Among the targets of pathophysiology research, amyloid-β continues to be the focus of greatest interest, with tau and apolipoprotein E stagnant after a surge in the 1990s. The role of inflammation, microglia, and the synapse are other research topics with growing interest. Regarding preventative strategies, education attainment, diet, and exercise are recently gaining some momentum, whereas NSAIDs and statins have lost the spotlight they once had.ConclusionOur bibliometric and scientometric analysis provides distinct trends in AD research in the last four decades, including publication and patent output, funding, impact, and topics. Our findings could inform the decision-making of research funding agencies in the near future.
| S-EPMC6002842 | biostudies-literature
Project description:The causal role of abdominal overweight/obesity, insulin resistance and type 2 diabetes (T2D) on the risk of fatty liver disease (FLD) has robustly been proven. A consensus of experts has recently proposed the novel definition of 'metabolic dysfunction-associated fatty liver disease, MAFLD' instead of 'nonalcoholic fatty liver disease, NAFLD', emphasizing the central role of dysmetabolism in the disease pathogenesis. Conversely, a direct and independent contribution of FLD per se on risk of developing T2D is still a controversial topic. When dealing with FLD as a potential risk factor for T2D, it is straightforward to think of hepatic insulin resistance as the most relevant underlying mechanism. Emerging evidence supports genetic determinants of FLD (eg PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13) as determinants of insulin resistance and T2D. However, recent studies highlighted that the key molecular mechanism of dysmetabolism is not fat accumulation per se but the degree of hepatic fibrosis (excess liver fat content-lipotoxicity), leading to reduced insulin clearance, insulin resistance and T2D. A consequence of these findings is that drugs that will ameliorate liver fat accumulation and fibrosis in principle may also exert a beneficial effect on insulin resistance and risk of T2D in individuals with FLD. Finally, initial findings show that these genetic factors might be directly implicated in modulating pancreatic beta-cell function, although future studies are needed to fully understand this relationship.
| S-EPMC7576307 | biostudies-literature
Project description:Huntington's disease (HD), a dominantly inherited neurodegenerative disease, is defined by its genetic cause, a CAG-repeat expansion in the HTT gene, its motor and psychiatric symptomology and primary loss of striatal medium spiny neurons (MSNs). However, the molecular mechanisms from genetic lesion to disease phenotype remain largely unclear. Mouse models of HD have been created that exhibit phenotypes partially recapitulating those in the patient, and specifically, cortico-striatal disconnectivity appears to be a shared pathogenic event shared by HD mouse models and patients. Molecular studies have begun to unveil converging molecular and cellular pathogenic mechanisms that may account for cortico-striatal miscommunication in various HD mouse models. Systems biological approaches help to illuminate synaptic molecular networks as a nexus for HD cortio-striatal pathogenesis, and may offer new candidate targets to modify the disease.
| S-EPMC5825262 | biostudies-literature