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Huntingtin disease

Koning Shen, Barbara Calamini, Jonathan A Fauerbach, Boxue Ma, Sarah H Shahmoradian, Ivana L Serrano Lachapel, Wah Chiu, Donald C Lo, Judith Frydman
Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington's disease (HD), neurotoxicity correlates with increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation...
October 18, 2016: ELife
Russell L Margolis, Dobrila D Rudnicki
PURPOSE OF REVIEW: Huntington's disease-like 2 (HDL2) is a rare, progressive, autosomal dominant neurodegenerative disorder that genetically, clinically, and pathologically closely resembles Huntington's disease. We review HDL2 pathogenic mechanisms and examine the implications of these mechanisms for Huntington's disease and related diseases. RECENT FINDINGS: HDL2 is caused by a CTG/CAG repeat expansion in junctophilin-3. Available data from cell and animal models and human brain suggest that HDL2 is a complex disease in which transcripts and proteins expressed bidirectionally from the junctophilin-3 locus contribute to pathogenesis through both gain-and loss-of-function mechanisms...
October 5, 2016: Current Opinion in Neurology
Kimberly A Quaid, Shirley W Eberly, Elise Kayson-Rubin, David Oakes, Ira Shoulson
Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a CAG triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length...
October 14, 2016: Clinical Genetics
Yoshihiro Kino, Chika Washizu, Masaru Kurosawa, Mizuki Yamada, Hiroshi Doi, Toru Takumi, Hiroaki Adachi, Masahisa Katsuno, Gen Sobue, Geoffrey G Hicks, Nobutaka Hattori, Tomomi Shimogori, Nobuyuki Nukina
FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington's disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS...
October 14, 2016: Scientific Reports
Wen Xi, Xin Wang, Thomas M Laue, Clyde L Denis
Huntington's disease (HD) results from expansions of polyglutamine stretches (polyQ) in the huntingtin protein (Htt) that promote protein aggregation, neurodegeneration, and death. Since the diversity and sizes of the soluble Htt-polyQ aggregates that have been linked to cytotoxicity are unknown, we investigated soluble Htt-polyQ aggregates using analytical ultracentrifugation. Soon after induction in a yeast HD model system, non-toxic Htt-25Q and cytotoxic Htt-103Q both formed soluble aggregates 29S to 200S in size...
October 10, 2016: Scientific Reports
Laura Rué, Mónica Bañez-Coronel, Jordi Creus-Muncunill, Albert Giralt, Rafael Alcalá-Vida, Gartze Mentxaka, Birgit Kagerbauer, M Teresa Zomeño-Abellán, Zeus Aranda, Veronica Venturi, Esther Pérez-Navarro, Xavier Estivill, Eulàlia Martí
Huntington's disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid-modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels...
October 10, 2016: Journal of Clinical Investigation
Beatriz Galan-Rodriguez, Elodie Martin, Emmanuel Brouillet, Nicole Déglon, Sandrine Betuing, Jocelyne Caboche
Huntington's Disease, an inherited neurodegenerative disorder, results from abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted in synergy with expanded huntingtin to increase aggregates formation and striatal death through activation of the Rho/ROCK signaling pathway. In vivo, in a lentiviral-mediated model of expanded huntingtin expression in the rat striatum, we found that the D2 antagonist haloperidol protects striatal neurons against expanded huntingtin -mediated toxicity...
September 26, 2016: European Journal of Neuroscience
Fiona C A Geraerts, Russell G Snell, Richard L M Faull, Liam Williams, Jessie C Jacobsen, Suzanne J Reid
Huntington's disease is caused by expansion of the CAG repeat in Huntingtin. This repeat has shown tissue-specific instability in mouse models and in a small number of post-mortem human samples. We used small-pool PCR to generate a modified instability index to quantify CAG instability within two brain regions from six human samples where cell loss has been associated with motor and mood symptoms: the motor cortex and cingulate gyrus. The expanded allele demonstrated instability in both regions, with minimal instability in the unexpanded allele...
October 1, 2016: Journal of Huntington's Disease
Saida Abounit, Jessica W Wu, Guiliana Soraya Victoria, Chiara Zurzolo
The mechanisms of intercellular spreading of amyloidogenic proteins involved in neurodegenerative diseases have yet to be fully elucidated. While secretion has been implicated in the transfer of many proteins, including prions and α-synuclein, tunneling nanotubes (TNTs) have also been demonstrated for prions and mutant Huntingtin. Here, we provide further evidence that Tau aggregates, which have been demonstrated to predominantly be transferred via secretion, can also be found in TNTs. Additionally cells that have taken up Tau have increased TNT formation...
October 7, 2016: Prion
M Rodríguez-Arribas, S M S Yakhine-Diop, J M Bravo-San Pedro, P Gómez-Suaga, R Gómez-Sánchez, G Martínez-Chacón, J M Fuentes, R A González-Polo, M Niso-Santano
Mitochondria-associated membranes (MAMs) are structures that regulate physiological functions between endoplasmic reticulum (ER) and mitochondria in order to maintain calcium signaling and mitochondrial biogenesis. Several proteins located in MAMs, including those encoded by PARK genes and some of neurodegeneration-related proteins (huntingtin, presenilin, etc.), ensure this regulation. In this regard, MAM alteration is associated with neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD) and contributes to the appearance of the pathogenesis features, i...
October 6, 2016: Molecular Neurobiology
Sonali Lokhande, Biranchi N Patra, Animesh Ray
Huntington's disease is a rare neurodegenerative disorder whose complex pathophysiology exhibits system-wide changes in the body, with striking and debilitating clinical features targeting the central nervous system. Among the various molecular functions affected in this disease, mitochondrial dysfunction and transcriptional dysregulation are some of the most studied aspects of this disease. However, there is evidence of the involvement of a mutant Huntingtin protein in the processes of DNA damage, chromosome condensation and DNA repair...
September 29, 2016: Molecular BioSystems
Sara Sameni, Adeela Syed, J Lawrence Marsh, Michelle A Digman
Huntington disease (HD) is an autosomal neurodegenerative disorder caused by the expansion of Polyglutamine (polyQ) in exon 1 of the Huntingtin protein. Glutamine repeats below 36 are considered normal while repeats above 40 lead to HD. Impairment in energy metabolism is a common trend in Huntington pathogenesis; however, this effect is not fully understood. Here, we used the phasor approach and Fluorescence Lifetime Imaging Microscopy (FLIM) to measure changes between free and bound fractions of NADH as a indirect measure of metabolic alteration in living cells...
October 7, 2016: Scientific Reports
Wen-Juan Huang, Wei-Wei Chen, Xia Zhang
Huntington's disease (HD) is a frequent and incurable hereditary neurodegenerative disorder that impairs motor and cognitive functions. Mutations in huntingtin (HTT) protein, which is essential for neuronal development, lead to the development of HD. An increase in the number of CAG repeats within the HTT gene, which lead to an expansion of polyglutamine tract in the resulting mutated HTT protein, which is toxic, is the causative factor of HD. Although the molecular basis of HD is known, there is no known cure for this disease other than symptomatic relief treatment approaches...
October 2016: Experimental and Therapeutic Medicine
Allison M Keeler, Ellen Sapp, Kathryn Chase, Emily Sottosanti, Eric Danielson, Edith Pfister, Lorelei Stoica, Marian DiFiglia, Neil Aronin, Miguel Sena-Esteves
BACKGROUND: The genetic mutation in Huntington's disease (HD) is a CAG repeat expansion in the coding region of the huntingtin (Htt) gene. RNAi strategies have proven effective in substantially down-regulating Htt mRNA in the striatum through delivery of siRNAs or viral vectors based on whole tissue assays, but the extent of htt mRNA lowering in individual neurons is unknown. OBJECTIVE: Here we characterize the effect of an AAV9-GFP-miRHtt vector on Htt mRNA levels in striatal neurons of Q140/Q140 knock-in mice...
October 1, 2016: Journal of Huntington's Disease
Petr Vodicka, Kathryn Chase, Maria Iuliano, Adelaide Tousley, Dana T Valentine, Ellen Sapp, Kimberly B Kegel-Gleason, Miguel Sena-Esteves, Neil Aronin, Marian DiFiglia
BACKGROUND: Mutant huntingtin (mHTT) is encoded by the Huntington's disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy. OBJECTIVE: To examine if increasing TFEB protein levels in HD mouse striatum induces autophagy and influences mHTT levels. METHODS: We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9...
October 1, 2016: Journal of Huntington's Disease
Ashley A Zurawel, Ruth Kabeche, Sonja E DiGregorio, Lin Deng, Kartikeya M Menon, Hannah Opalko, Martin L Duennwald, James B Moseley, Surachai Supattapone
: Proteins containing polyglutamine (polyQ) regions are found in almost all eukaryotes, albeit with various frequencies. In humans, proteins such as huntingtin (Htt) with abnormally expanded polyQ regions cause neurodegenerative diseases such as Huntington's disease (HD). To study how the presence of endogenous polyQ aggregation modulates polyQ aggregation and toxicity, we expressed polyQ expanded Htt fragments (polyQ Htt) in Schizosaccharomyces pombe In stark contrast to other unicellular fungi, such as Saccharomyces cerevisiae, S...
September 27, 2016: MBio
Géraldine Liot, Julien Valette, Jérémy Pépin, Julien Flament, Emmanuel Brouillet
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt)...
September 14, 2016: Biochemical and Biophysical Research Communications
João Casaca-Carreira, Lodewijk J A Toonen, Melvin M Evers, Ali Jahanshahi, Willeke M C van-Roon-Mom, Yasin Temel
Huntington's disease (HD) is a progressive autosomal dominant disease, caused by a CAG repeat expansion in the HTT gene, resulting in an expanded polyglutamine stretch at the N-terminal of the huntingtin protein. An important event in HD pathogenesis appears to be the proteolysis of the mutant protein, which forms N-terminal huntingtin fragments. These fragments form insoluble aggregates and are found in nuclei and cytoplasm of affected neurons where they interfere with normal cell functioning. Important cleavage sites are encoded by exon 12 of HTT...
September 15, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Danielle A Simmons, Nadia P Belichenko, Ellen C Ford, Sarah Semaan, Marie Monbureau, Sruti Aiyaswamy, Cameron M Holman, Christina Condon, Mehrdad Shamloo, Stephen M Massa, Frank M Longo
Decreases in the ratio of neurotrophic versus neurodegenerative signaling play a critical role in Huntington's disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75(NTR) signaling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75(NTR)-associated deleterious signaling and decreases survival signaling suggesting that p75(NTR) could be a valuable therapeutic target...
September 16, 2016: Human Molecular Genetics
Rodrigo A Quintanilla, Cheril Tapia, María José Pérez
Huntington disease (HD) is a devastating neurological disorder that affects the striatum and cortex of patients. HD patients develop progressive motor dysfunction and psychiatric disturbances with gradual dementia. HD is caused by a pathological expansion of CAG repeats in the huntingtin gene that codifies for a protein called huntingtin (Htt), which principal function is not completely understood. Accumulative evidence shows that this pathological expansion modifies Htt function affecting different neuronal targets, including mitochondrial function which is an important factor that contributes to HD...
September 13, 2016: Biochemical and Biophysical Research Communications
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