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Kinga Hadzsiev, Mónika Szőts, Anett Fekete, László Balikó, Kim Boycott, Ferenc Nagy, Béla Melegh
In a patient with marked symptoms of Huntington disease after the huntingtin testing, which gave normal result, a whole exome sequencing (WES) has been performed based on an international collaboration. A homozygous G>A nucleotid change in the exon 34 of the VPS13A gene has been detected with WES, a mutation resulting in a premature stop codon at the position 1301. This change is a known pathogenic mutation. The aim of this article is to draw attention on the importance of the WES in the diagnosis of rare neurological diseases without any specific symptoms...
October 2017: Orvosi Hetilap
Caitlin S Latimer, Margaret E Flanagan, Patrick J Cimino, Suman Jayadev, Marie Davis, Zachary S Hoffer, Thomas J Montine, Luis F Gonzalez-Cuyar, Thomas D Bird, C Dirk Keene
BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in huntingtin (HTT) on chromosome 4. Anticipation can cause longer repeat expansions in children of HD patients. Juvenile Huntington's disease (JHD), defined as HD arising before age 20, accounts for 5-10% of HD cases, with cases arising in the first decade accounting for approximately 1%. Clinically, JHD differs from the predominately choreiform adult onset Huntington's disease (AOHD) with variable presentations, including symptoms such as myoclonus, seizures, Parkinsonism, and cognitive decline...
October 11, 2017: Journal of Huntington's Disease
Richard G Yau, Kerstin Doerner, Erick R Castellanos, Diane L Haakonsen, Achim Werner, Nan Wang, X William Yang, Nadia Martinez-Martin, Marissa L Matsumoto, Vishva M Dixit, Michael Rape
Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood...
October 11, 2017: Cell
Marie-France Paré, Bernard J Jasmin
Huntington's disease (HD) is an autosomal dominant neurodegenerative genetic disorder characterized by motor, cognitive, and psychiatric symptoms. It is well established that regular physical activity supports brain health, benefiting cognitive function, mental health as well as brain structure and plasticity. Exercise mimetics (EMs) are a group of drugs and small molecules that target signaling pathways in skeletal muscle known to be activated by endurance exercise. The EM 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) has been shown to induce cognitive benefits in healthy mice...
2017: Frontiers in Neurology
Lorena B Areal, Lorraine P Pereira, Fabiola M Ribeiro, Isabella G Olmo, Marcelo R Muniz, Maria do Carmo Rodrigues, Patrik F Costa, Cristina Martins-Silva, Stephen S G Ferguson, Daniela A M Guimarães, Rita G W Pires
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive deficits, and psychiatric symptoms. The primary genetic cause is an expansion of cytosine adenine guanine (CAG) nucleotides of the huntingtin gene, which codes an important protein involved with neuronal signaling. The severity of HD correlates with the number of CAG repeats and individuals with longer expansions have an earlier onset and more severe symptoms. A microarray study conducted by our research group showed alteration in DNAH6 gene (encoding dynein axonemal heavy chain 6)...
October 10, 2017: Journal of Molecular Neuroscience: MN
Melanie Alpaugh, Danny Galleguillos, Juan Forero, Luis Carlos Morales, Sebastian W Lackey, Preeti Kar, Alba Di Pardo, Andrew Holt, Bradley J Kerr, Kathryn G Todd, Glen B Baker, Karim Fouad, Simonetta Sipione
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD In this study, we provide evidence that intraventricular administration of GM1 has profound disease-modifying effects across HD mouse models with different genetic background...
October 9, 2017: EMBO Molecular Medicine
Bo Wang, Li Zeng, Sean A Merillat, Joseph Ochaba, Leslie M Thompson, Sami J Barmada, Kenneth M Scaglione, Henry L Paulson
Huntington's disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ) expansion in the HD disease protein, huntingtin (HTT). PolyQ expansion promotes misfolding and aggregation of mutant HTT (mHTT) within neurons. The cellular pathways, including ubiquitin-dependent processes, by which mHTT is regulated remain incompletely understood. Ube2W is the only ubiquitin conjugating enzyme (E2) known to ubiquitinate substrates at their amino (N)-termini, likely favoring substrates with disordered N-termini...
October 3, 2017: Neurobiology of Disease
Wojciech J Szlachcic, Kalina Wiatr, Marta Trzeciak, Marek Figlerowicz, Maciej Figiel
[This corrects the article on p. 253 in vol. 10, PMID: 28848389.].
2017: Frontiers in Molecular Neuroscience
Xiaoli Sun, Yuhua Fu, Yuyin Pan, Boxun Lu
Protein misfolding is the common theme for neurodegenerative disorders including Huntington's Disease (HD), which is mainly caused by cytotoxicity of the mutant HTT (huntingtin) protein (mHTT). The soluble mHTT has an expanded polyglutamine (polyQ) stretch that may adopt multiple conformations, among which the one recognized by the polyQ antibody 3B5H10 is the most toxic due to unknown mechanisms. In a recent study, we showed that the 3B5H10-recognized mHTT species has a slower degradation rate due to its resistance to selective macroautophagy/autophagy...
October 4, 2017: Autophagy
Haiying Liu, Chunqiu Dai, Yunlong Fan, Baolin Guo, Keke Ren, Tangna Sun, Wenting Wang
P62, also called sequestosome1 (SQSTM1), is the selective cargo receptor for autophagy to degenerate misfolded proteins. It has also been found to assist and connect parkin in pink1/parkin mitophagy pathway. Previous studies showed that p62 was in association with neurodegenerative diseases, and one of the diseases pathogenesis is P62 induced autophagy and mitophagy dysfunction. Autophagy is an important process to eliminate misfolded proteins. Intracellular aggregation including α-synuclein, Huntingtin, tau protein and ß-amyloid (Aß) protein are the misfolded proteins found in PD, HD and AD, respectively...
October 3, 2017: Journal of Bioenergetics and Biomembranes
Ali Khoshnan, Adam Sabbaugh, Barbara Calamini, Steven A Marinero, Denise E Dunn, Jung Hyun Yoo, Jan Ko, Donald C Lo, Paul H Patterson
Neuronal interleukin-34 (IL-34) promotes the expansion of microglia in the central nervous system-microglial activation and expansion are in turn implicated in the pathogenesis of Huntington's disease (HD). We thus examined whether the accumulation of an amyloidogenic exon-1 fragment of mutant huntingtin (mHTTx1) modulates the expression of IL-34 in dopaminergic neurons derived from a human embryonic stem cell line. We found that mHTTx1 aggregates induce IL-34 production selectively in post-mitotic neurons...
August 14, 2017: Human Molecular Genetics
Nicolas Arbez, Tamara Ratovitski, Elaine Roby, Ekaterine Chighladze, Jacqueline Stewart, Mark Ren, Xiaofang Wang, Daniel J Lavery, Christopher A Ross
Huntington's disease (HD) is caused in large part by a polyglutamine expansion within the huntingtin (Htt) protein. Posttranslational modifications (PTMs) control and regulate many protein functions and cellular pathways, and PTMs of mutant Htt are likely important modulators of HD pathogenesis. Alterations of a selected numbers of PTMs of Htt fragments have been shown to modulate Htt cellular localization and toxicity. In this study, we systematically introduced site-directed alterations in individual phosphorylation and acetylation sites in full-length Htt constructs...
September 27, 2017: Journal of Biological Chemistry
Nelina P Angelova
This paper aims to study four general hallmarks of neurodegeneration and the correlations between them, with emphasis on the huntingtin (htt) interactions contributing to their prevention or promotion in its wild-type and mutated forms. Most of the neurodegenerative diseases share same or similar cell dysfunctions and huntingtin seems to associate in an polyglutamine-length dependent manner with components of the mechanisms that can go impaired. Therefore, the protein is proposed as contributing factor to the development of selective neurodegeneration...
2017: Advances in Experimental Medicine and Biology
Francesca R Fusco, Emanuela Paldino
Huntington's disease (HD) is an autosomal-dominant rare inherited neurodegenerative disease characterized by a wide variety of symptoms encompassing movement, cognition and behaviour. The cause of the disease is a genetic mutation in the huntingtin protein. The mutation leads to an unstable CAG expansion, translated into a polyglutamine domain within the disease protein. Indeed, huntingtin has a CAG/polyglutamine expansion in the range of 6-39 units in normal individuals, whereas it reaches 39-180 units in HD patients...
2017: Advances in Neurobiology
Lindsay Romo, Ami Ashar-Patel, Edith Pfister, Neil Aronin
The huntingtin gene has two mRNA isoforms that differ in their 3' UTR length. The relationship of these isoforms with Huntington's disease is not established. We provide evidence that the abundance of huntingtin 3' UTR isoforms differs between patient and control neural stem cells, fibroblasts, motor cortex, and cerebellum. Huntingtin 3' UTR isoforms, including a mid-3' UTR isoform, have different localizations, half-lives, polyA tail lengths, microRNA sites, and RNA-binding protein sites. Isoform shifts in Huntington's disease motor cortex are not limited to huntingtin; 11% of alternatively polyadenylated genes change the abundance of their 3' UTR isoforms...
September 26, 2017: Cell Reports
Fernando Pagan, Yasar Torres-Yaghi, Marcelle Altshuler
Huntington disease (HD) is an autosomal-dominant disorder resulting from CAG triplet repeats, which leads to an expanded polyglutamine sequence in the HTT (Huntingtin) protein. Accumulation of the Huntingtin protein ultimately leads to neurodegeneration and negative effects in multiple clinical domains, including motor function, cognition, and behavior. HD is a disorder governed by genetics, and the ability to quantify the CAG triplet repeats can provide important insight regarding clinical onset, severity, and disease progression...
2017: Handbook of Clinical Neurology
Tanya P Garcia, Karen Marder, Yuanjia Wang
Huntington disease (HD) is caused by a CAG trinucleotide expansion in the huntingtin gene. We now have the power to predict age-at-onset from subject-specific features like motor and neuroimaging measures. In clinical trials, properly modeling onset age is important, because it improves power calculations and directs clinicians to recruit subjects with certain features. The history of modeling onset, from simple linear and logistic regression to advanced survival models, is discussed. We highlight their advantages and disadvantages, emphasizing the methodological challenges when genetic mutation status is unavailable...
2017: Handbook of Clinical Neurology
Martha A Nance
In this chapter, we review the evolution of our understanding of the genetic aspects of HD, and the applications of our understanding in the management of Huntington's disease patients and families over the last 150 years. Important aspects of the clinical genetics and epidemiology of Huntington's disease are discussed, such as the definition of "normal" and "abnormal" numbers of CAG (cytosine-adenine-guanine) repeats in the critical spot within the huntingtin gene, meiotic instability of CAG repeat numbers, common Huntington's disease genetic haplotypes, compound heterozygosity for an abnormal gene, and somatic mosaicism for CAG repeat expansions...
2017: Handbook of Clinical Neurology
Anindita Deb, Samuel Frank, Claudia M Testa
Huntington disease (HD), an inherited neurodegenerative disease, results from a CAG repeat expansion creating mutant huntingtin protein and widespread neuronal damage. Motor symptoms such as chorea are often preceded by cognitive and behavioral changes. Tetrabenazine and deutetrabebenazine are the two drugs approved by the Federal Food and Drug Administrationfor HD symptoms, is an effective therapy for chorea. However, there is still a large need for other symptomatic therapies impacting functional issues, including impaired gait, behavioral, and cognitive symptoms...
2017: Handbook of Clinical Neurology
Christopher A Ross, Martin Kronenbuerger, Wenzhen Duan, Russell L Margolis
The CAG repeat expansion mutation that causes Huntington Disease (HD) was discovered more than 20 years ago, yet no treatment has yet been developed to stop the relentless course of the disease. Nonetheless, substantial progress has been made in understanding HD pathogenesis. We review insights that have been gleaned from HD genetics, metabolism, and pathology; HD mouse and cell models; the structure, function and post-translational modification of normal and mutant huntingtin (htt) protein; gene expression profiles in HD cells and tissue; the neurotoxicy of mutant htt RNA; and the expression of an antisense transcript from the HD locus...
2017: Handbook of Clinical Neurology
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