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https://www.readbyqxmd.com/read/28633380/epigallocatechin-3-gallate-and-related-phenol-compounds-redirect-the-amyloidogenic-aggregation-pathway-of-ataxin-3-towards-non-toxic-aggregates-and-prevent-toxicity-in-neural-cells-and-caenorhabditis-elegans-animal-model
#1
Cristina Visentin, Francesca Pellistri, Antonino Natalello, Jacopo Vertemara, Marcella Bonanomi, Elena Gatta, Amanda Penco, Annalisa Relini, Luca De Gioia, Cristina Airoldi, Maria E Regonesi, Paolo Tortora
The protein ataxin-3 (ATX3) triggers an amyloid-related neurodegenerative disease when its polyglutamine stretch is expanded beyond a critical threshold. We formerly demonstrated that the polyphenol epigallocatechin-3-gallate (EGCG) could redirect amyloid aggregation of a full-length, expanded ATX3 (ATX3-Q55) towards non-toxic, soluble, SDS-resistant aggregates. Here, we have characterized other related phenol compounds, although smaller in size, i.e., (-)-epigallocatechin gallate (EGC), and gallic acid (GA)...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28629183/an-amyloidogenic-sequence-at-the-n-terminus-of-the-androgen-receptor-impacts-polyglutamine-aggregation
#2
Emmanuel Oppong, Gunter Stier, Miriam Gaal, Rebecca Seeger, Melanie Stoeck, Marc-André Delsuc, Andrew C B Cato, Bruno Kieffer
The human androgen receptor (AR) is a ligand inducible transcription factor that harbors an amino terminal domain (AR-NTD) with a ligand-independent activation function. AR-NTD is intrinsically disordered and displays aggregation properties conferred by the presence of a poly-glutamine (polyQ) sequence. The length of the polyQ sequence as well as its adjacent sequence motifs modulate this aggregation property. AR-NTD also contains a conserved KELCKAVSVSM sequence motif that displays an intrinsic property to form amyloid fibrils under mild oxidative conditions...
June 19, 2017: Biomolecules
https://www.readbyqxmd.com/read/28609090/emerging-%C3%AE-sheet-rich-conformations-in-super-compact-huntingtin-exon-1-mutant-structures
#3
Hongsuk Kang, Francisco X Vázquez, Leili Zhang, Payel Das, Leticia Marisel Toledo-Sherman, Binquan Luan, Michael Levitt, Ruhong Zhou
There exits strong correlation between the extended poly-glutamines (polyQ) within exon-1 of Huntingtin protein (Htt) and age onset of Huntington's disease (HD), however, the underlying molecular mechanism is still poorly understood. Here we apply extensive molecular dynamics simulations to study the folding of Htt-exon-1 across five different polyQ-lengths. We find an increase in secondary structure motifs at longer Q-lengths, including β-sheet content that seems to contribute to the formation of increasingly compact structures...
June 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28596723/the-11s-proteasomal-activator-reg%C3%AE-impacts-polyglutamine-expanded-androgen-receptor-aggregation-and-motor-neuron-viability-through-distinct-mechanisms
#4
Jill M Yersak, Heather L Montie, Erica S Chevalier-Larsen, Yuhong Liu, Lan Huang, Martin Rechsteiner, Diane E Merry
Spinal and bulbar muscular atrophy (SBMA) is caused by expression of a polyglutamine (polyQ)-expanded androgen receptor (AR). The inefficient nuclear proteasomal degradation of the mutant AR results in the formation of nuclear inclusions containing amino-terminal fragments of the mutant AR. PA28γ (also referred to as REGγ) is a nuclear 11S-proteasomal activator with limited proteasome activation capabilities compared to its cytoplasmic 11S (PA28α, PA28β) counterparts. To clarify the role of REGγ in polyQ-expanded AR metabolism, we carried out genetic and biochemical studies in cell models of SBMA...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28590448/striatal-vulnerability-in-huntington-s-disease-neuroprotection-versus-neurotoxicity
#5
REVIEW
Ryoma Morigaki, Satoshi Goto
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities...
June 7, 2017: Brain Sciences
https://www.readbyqxmd.com/read/28545543/inhibition-of-colony-stimulating-factor-1-receptor-early-in-disease-ameliorates-motor-deficits-in-sca1-mice
#6
Wenhui Qu, Andrea Johnson, Joo Hyun Kim, Abigail Lukowicz, Daniel Svedberg, Marija Cvetanovic
BACKGROUND: Polyglutamine (polyQ) expansion in the protein Ataxin-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a fatal dominantly inherited neurodegenerative disease characterized by motor deficits, cerebellar neurodegeneration, and gliosis. Currently, there are no treatments available to delay or ameliorate SCA1. We have examined the effect of depleting microglia during the early stage of disease by using PLX, an inhibitor of colony-stimulating factor 1 receptor (CSFR1), on disease severity in a mouse model of SCA1...
May 25, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28542401/molecular-dynamics-analysis-of-the-aggregation-propensity-of-polyglutamine-segments
#7
Jingran Wen, Daniel R Scoles, Julio C Facelli
Protein misfolding and aggregation is a pathogenic feature shared among at least ten polyglutamine (polyQ) neurodegenerative diseases. While solvent-solution interaction is a key factor driving protein folding and aggregation, the solvation properties of expanded polyQ tracts are not well understood. By using GPU-enabled all-atom molecular dynamics simulations of polyQ monomers in an explicit solvent environment, this study shows that solvent-polyQ interaction propensity decreases as the lengths of polyQ tract increases...
2017: PloS One
https://www.readbyqxmd.com/read/28539049/assembly-of-huntingtin-headpiece-into-%C3%AE-helical-bundles
#8
Beytullah Ozgur, Mehmet Sayar
Protein aggregation is a hallmark of neurodegenerative disorders. In this group of brain-related disorders, a disease-specific "host" protein or fragment misfolds and adopts a metastatic, aggregate-prone conformation. Often, this misfolded conformation is structurally and thermodynamically different from its native state. Intermolecular contacts, which arise in this non-native state, promote aggregation. In this regard, understanding the molecular principles and mechanisms that lead to the formation of such a non-native state and further promote the formation of the critical nucleus for fiber growth is essential...
May 24, 2017: Biointerphases
https://www.readbyqxmd.com/read/28532681/resveratrol-protects-neuronal-like-cells-expressing-mutant-huntingtin-from-dopamine-toxicity-by-rescuing-atg4-mediated-autophagosome-formation
#9
Chiara Vidoni, Eleonora Secomandi, Andrea Castiglioni, Mariarosa A B Melone, Ciro Isidoro
Parkinsonian-like motor deficits in Huntington's Disease (HD) patients are associated with abnormal dopamine neurotransmission in the striatum. Dopamine metabolism leads to the formation of oxidized dopamine quinones that exacerbates mitochondrial dysfunction with production of reactive oxygen species (ROS) that eventually lead to neuronal cell death. We have previously shown that dopamine-induced oxidative stress triggers apoptotic cell death in dopaminergic neuroblastoma SH-SY5Y cells hyper-expressing the mutant polyQ Huntingtin (polyQ-Htt) protein...
May 19, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28531354/monomeric-polyglutamine-structures-that-evolve-into-fibrils
#10
David Punihaole, Ryan S Jakubek, Riley J Workman, Lauren E Marbella, Patricia Campbell, Jeffry D Madura, Sanford A Asher
We investigate the solution and fibril conformations and structural transitions of the polyglutamine (polyQ) peptide, D2Q10K2 (Q10), by synergistically using UV resonance Raman (UVRR) spectroscopy and molecular dynamics (MD) simulations. We show that Q10 adopts two distinct, monomeric solution conformational states: a collapsed β-strand and a PPII-like structure that do not readily interconvert. This clearly indicates a high activation barrier in solution that prevents equilibration between these structures...
June 8, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28527524/c9orf72-hexanucleotide-repeat-expansions-and-ataxin-2-intermediate-length-repeat-expansions-in-indian-patients-with-amyotrophic-lateral-sclerosis
#11
Priyam Narain, James Gomes, Rohit Bhatia, Inder Singh, Perumal Vivekanandan
Repeat expansions in the chromosome 9 open reading frame 72 (C9orf72) gene have been recognized as a major contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in the Caucasian population. Intermediate length repeat expansions of CAG (polyQ) repeat in the ATXN2 gene have also been reported to increase the risk of developing ALS in North America and Europe. We screened 131 ALS patients and 127 healthy controls from India for C9orf72 and ATXN2 repeat expansions. We found pathogenic hexanucleotide expansions in 3 of the 127 sporadic ALS patients, in 1 of the 4 familial ALS patients, and in none of the healthy controls...
April 26, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28525545/gene-co-expression-network-analysis-for-identifying-modules-and-functionally-enriched-pathways-in-sca2
#12
Lance T Pflieger, Warunee Dansithong, Sharan Paul, Daniel Scoles, Karla P Figueroa, Pratap Meera, Thomas S Otis, Julio C Facelli, Stefan M Pulst
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the ATXN2 gene. The repeat resides in an encoded region of the gene resulting in polyglutamine (polyQ) expansion which has been assumed to result in gain of function, predominantly, for the ATXN2 protein. We evaluated temporal cerebellar expression profiles by RNA sequencing of ATXN2Q127 mice vs wildtype littermates. ATXN2Q127 mice are characterized by a progressive motor phenotype onset, and have progressive cerebellar molecular and neurophysiological (Purkinje cell firing frequency) phenotypes...
May 19, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28524599/modulation-of-nuclear-rest-by-alternative-splicing-a-potential-therapeutic-target-for-huntington-s-disease
#13
Guo-Lin Chen, Qi Ma, Dharmendra Goswami, Jianyu Shang, Gregory M Miller
Huntington's disease (HD) is caused by a genetically mutated huntingtin (mHtt) protein with expanded polyQ stretch, which impairs cytosolic sequestration of the repressor element-1 silencing transcription factor (REST), resulting in excessive nuclear REST and subsequent repression of neuronal genes. We recently demonstrated that REST undergoes extensive, context-dependent alternative splicing, of which exon-3 skipping (∆E3 )-a common event in human and nonhuman primates-causes loss of a motif critical for REST nuclear targeting...
May 19, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28511915/altered-ionic-currents-and-amelioration-by-igf-1-and-pacap-in-motoneuron-derived-cells-modelling-sbma
#14
Aura M Jiménez Garduño, Leon J Juárez-Hernández, María J Polanco, Laura Tosatto, Daniela Michelatti, Daniele Arosio, Manuela Basso, Maria Pennuto, Carlo Musio
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a motor neuron disease caused by the expansion of a polymorphic CAG tandem repeat encoding a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. SBMA is triggered by the binding of mutant AR to its natural ligands, testosterone and dihydrotestosterone (DHT). To investigate the neuronal alterations of motor neuron cell models of SBMA, we applied patch-clamp methods to verify how polyQ expansions in the AR alter cell ionic currents...
May 10, 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/28503130/uncoupling-the-trade-off-between-somatic-proteostasis-and-reproduction-in-caenorhabditis-elegans-models-of-polyglutamine-diseases
#15
Netta Shemesh, Nadav Shai, Lana Meshnik, Rotem Katalan, Anat Ben-Zvi
Caenorhabditis elegans somatic protein homeostasis (proteostasis) is actively remodeled at the onset of reproduction. This proteostatic collapse is regulated cell-nonautonomously by signals from the reproductive system that transmit the commitment to reproduction to somatic cells. Here, we asked whether the link between the reproductive system and somatic proteostasis could be uncoupled by activating downstream effectors in the gonadal longevity cascade. Specifically, we examined whether over-expression of lipl-4 (lipl-4(oe)), a target gene of the gonadal longevity pathway, or increase in arachidonic acid (AA) levels, associated with lipl-4(oe), modulated proteostasis and reproduction...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28499347/the-dynamics-of-early-state-transcriptional-changes-and-aggregate-formation-in-a-huntington-s-disease-cell-model
#16
Martijn van Hagen, Diewertje G E Piebes, Wim C de Leeuw, Ilona M Vuist, Willeke M C van Roon-Mom, Perry D Moerland, Pernette J Verschure
BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. Proteolytic cleavage of mutant huntingtin (Htt) protein with an expanded polyglutamine (polyQ) stretch results in production of Htt fragments that aggregate and induce impaired ubiquitin proteasome, mitochondrial functioning and transcriptional dysregulation. To understand the time-resolved relationship between aggregate formation and transcriptional changes at early disease stages, we performed temporal transcriptome profiling and quantification of aggregate formation in living cells in an inducible HD cell model...
May 12, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28488702/mechanisms-of-diseases-excessive-polyq-tracts-curb-autophagy
#17
Paulina Strzyz
No abstract text is available yet for this article.
June 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28473226/kennedy-disease-x-linked-recessive-bulbospinal-neuronopathy-a-comprehensive-review-from-pathophysiology-to-therapy
#18
REVIEW
G Querin, G Sorarù, P-F Pradat
Kennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by expansion of a CAG repeat sequence in exon 1 of the androgen receptor gene (AR) encoding a polyglutamine (polyQ) tract. The polyQ-expanded AR accumulates in nuclei, and initiates degeneration and loss of motor neurons and dorsal root ganglia. While the disease has long been considered a pure lower motor neuron disease, recently, the presence of major hyper-creatine-kinase (CK)-emia and myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide range of clinical manifestations...
May 1, 2017: Revue Neurologique
https://www.readbyqxmd.com/read/28453707/the-role-of-ar-polyq-tract-in-male-breast-carcinoma-lesson-from-an-sbma-case
#19
G Querin, I Martinelli, C Bertolin, E Pegoraro, M Pennuto, G Sorarù
No abstract text is available yet for this article.
May 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28445460/polyglutamine-tracts-regulate-beclin-1-dependent-autophagy
#20
Avraham Ashkenazi, Carla F Bento, Thomas Ricketts, Mariella Vicinanza, Farah Siddiqi, Mariana Pavel, Ferdinando Squitieri, Maarten C Hardenberg, Sara Imarisio, Fiona M Menzies, David C Rubinsztein
Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing, causes toxicity...
May 4, 2017: Nature
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