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https://www.readbyqxmd.com/read/28753941/proteostasis-of-huntingtin-in-health-and-disease
#1
REVIEW
Seda Koyuncu, Azra Fatima, Ricardo Gutierrez-Garcia, David Vilchez
Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by motor dysfunction, cognitive deficits and psychosis. HD is caused by mutations in the Huntingtin (HTT) gene, resulting in the expansion of polyglutamine (polyQ) repeats in the HTT protein. Mutant HTT is prone to aggregation, and the accumulation of polyQ-expanded fibrils as well as intermediate oligomers formed during the aggregation process contribute to neurodegeneration. Distinct protein homeostasis (proteostasis) nodes such as chaperone-mediated folding and proteolytic systems regulate the aggregation and degradation of HTT...
July 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28743452/transcriptional-profiles-for-distinct-aggregation-states-of-mutant-huntingtin-exon-1-protein-unmask-new-huntington-s-disease-pathways
#2
Nagaraj S Moily, Angelique R Ormsby, Aleksandar Stojilovic, Yasmin M Ramdzan, Jeannine Diesch, Ross D Hannan, Michelle S Zajac, Anthony J Hannan, Alicia Oshlack, Danny M Hatters
Huntington's disease is caused by polyglutamine (polyQ)-expansion mutations in the CAG tandem repeat of the Huntingtin gene. The central feature of Huntington's disease pathology is the aggregation of mutant Huntingtin (Htt) protein into micrometer-sized inclusion bodies. Soluble mutant Htt states are most proteotoxic and trigger an enhanced risk of death whereas inclusions confer different changes to cellular health, and may even provide adaptive responses to stress. Yet the molecular mechanisms underpinning these changes remain unclear...
July 23, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28722507/polyglutamine-tracts-regulate-autophagy
#3
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
Expansions of polyglutamine (polyQ) tracts in different proteins cause 9 neurodegenerative conditions, such as Huntington disease and various ataxias. However, many normal mammalian proteins contain shorter polyQ tracts. As these are frequently conserved in multiple species, it is likely that some of these polyQ tracts have important but unknown biological functions. Here we review our recent study showing that the polyQ domain of the deubiquitinase ATXN3/ataxin-3 enables its interaction with BECN1/beclin 1, a key macroautophagy/autophagy initiator...
July 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28700938/golgi-outpost-synthesis-impaired-by-toxic-polyglutamine-proteins-contributes-to-dendritic-pathology-in-neurons
#4
Chang Geon Chung, Min Jee Kwon, Keun Hye Jeon, Do Young Hyeon, Myeong Hoon Han, Jeong Hyang Park, In Jun Cha, Jae Ho Cho, Kunhyung Kim, Sangchul Rho, Gyu Ree Kim, Hyobin Jeong, Jae Won Lee, TaeSoo Kim, Keetae Kim, Kwang Pyo Kim, Michael D Ehlers, Daehee Hwang, Sung Bae Lee
Dendrite aberration is a common feature of neurodegenerative diseases caused by protein toxicity, but the underlying mechanisms remain largely elusive. Here, we show that nuclear polyglutamine (polyQ) toxicity resulted in defective terminal dendrite elongation accompanied by a loss of Golgi outposts (GOPs) and a decreased supply of plasma membrane (PM) in Drosophila class IV dendritic arborization (da) (C4 da) neurons. mRNA sequencing revealed that genes downregulated by polyQ proteins included many secretory pathway-related genes, including COPII genes regulating GOP synthesis...
July 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28680391/the-role-of-the-multifunctional-bag3-protein-in-cellular-protein-quality-control-and-in-disease
#5
REVIEW
Elisabeth Stürner, Christian Behl
In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC) system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy). One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28673026/3%C3%AE-hydroxy-urs-12-en-28-oic-acid-modulates-dietary-restriction-mediated-longevity-and-ameliorates-toxic-protein-aggregation-in-c-elegans
#6
Hema Negi, Shilpi Khare Saikia, Rakesh Pandey
Species from lower invertebrates to a spectrum of mammals show anti-aging health benefits of phytochemical(s). Here, we explored the pro-longevity effects of a natural triterpenoid, ursolic acid (3β-hydroxy-urs-12-en-28-oic acid; UA) in Caenorhabditis elegans with maximal lifespan being evident at 25µM UA. Similar to eat-2 mutants, UA uptake by worm results in reduced fat storage and attenuation of reactive oxygen species (ROS), independent of superoxide dismutase(s) activation. The genetic requirements for UA mediated longevity are quite similar to dietary restriction (DR) achieved through SKN-1/ NRF-2 exhibiting up regulation of downstream target genes gcs-1 and daf-9...
June 30, 2017: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
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
#7
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
#8
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-supercompact-huntingtin-exon-1-mutant-structures
#9
Hongsuk Kang, Francisco X Vázquez, Leili Zhang, Payel Das, Leticia Toledo-Sherman, Binquan Luan, Michael Levitt, Ruhong Zhou
There exists strong correlation between the extended polyglutamines (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 23, 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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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