keyword
https://read.qxmd.com/read/38516767/targeted-degradation-of-hexokinase-2-for-anti%C3%A2-inflammatory-treatment-in-acute-lung-injury
#1
JOURNAL ARTICLE
Jiayan Yang, Liangliang Dong, Yifan Wang, Lifen Gong, Hongwei Gao, Yicheng Xie
Acute lung injury (ALI) is an acute inflammatory lung disease associated with both innate and adaptive immune responses. Hexokinase 2 (HK2) is specifically highly expressed in numerous types of inflammation‑related diseases and models. In the present study in vitro and in vivo effects of targeted degradation of HK2 on ALI were explored. The degradation of HK2 by the targeting peptide TAT (transactivator of transcription protein of HIV‑1)‑ataxin 1 (ATXN1)‑chaperone‑mediated autophagy‑targeting motif (CTM) was demonstrated by ELISA and western blotting in vitro and in vivo ...
May 2024: Molecular Medicine Reports
https://read.qxmd.com/read/38512434/mapping-sca1-regional-vulnerabilities-reveals-neural-and-skeletal-muscle-contributions-to-disease
#2
JOURNAL ARTICLE
Lisa Duvick, W Michael Southern, Kellie A Benzow, Zoe N Burch, Hillary P Handler, Jason S Mitchell, Hannah Kuivinen, Udaya Gadiparthi, Praseuth Yang, Alyssa Soles, Carrie A Sheeler, Orion Rainwater, Shannah Serres, Erin B Lind, Tessa Nichols-Meade, Brennon O'Callaghan, Huda Y Zoghbi, Marija Cvetanovic, Vanessa C Wheeler, James M Ervasti, Michael D Koob, Harry T Orr
Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockin mouse (f-ATXN1146Q/2Q) with mouse Atxn1 coding exons replaced by human ATXN1 exons encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival...
March 21, 2024: JCI Insight
https://read.qxmd.com/read/38125008/intranuclear-inclusions-of-polyq-expanded-atxn1-sequester-rna-molecules
#3
JOURNAL ARTICLE
Ioannis Gkekas, Aimilia-Christina Vagiona, Nikolaos Pechlivanis, Georgia Kastrinaki, Katerina Pliatsika, Sebastian Iben, Konstantinos Xanthopoulos, Fotis E Psomopoulos, Miguel A Andrade-Navarro, Spyros Petrakis
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in the ATXN1 gene. It is characterized by the presence of polyglutamine (polyQ) intranuclear inclusion bodies (IIBs) within affected neurons. In order to investigate the impact of polyQ IIBs in SCA1 pathogenesis, we generated a novel protein aggregation model by inducible overexpression of the mutant ATXN1(Q82) isoform in human neuroblastoma SH-SY5Y cells. Moreover, we developed a simple and reproducible protocol for the efficient isolation of insoluble IIBs...
2023: Frontiers in Molecular Neuroscience
https://read.qxmd.com/read/38016472/longitudinal-single-cell-transcriptional-dynamics-throughout-neurodegeneration-in-sca1
#4
JOURNAL ARTICLE
Leon Tejwani, Neal G Ravindra, Changwoo Lee, Yubao Cheng, Billy Nguyen, Kimberly Luttik, Luhan Ni, Shupei Zhang, Logan M Morrison, John Gionco, Yangfei Xiang, Jennifer Yoon, Hannah Ro, Fatema Haidery, Rosalie M Grijalva, Eunwoo Bae, Kristen Kim, Regina T Martuscello, Harry T Orr, Huda Y Zoghbi, Hayley S McLoughlin, Laura P W Ranum, Vikram G Shakkottai, Phyllis L Faust, Siyuan Wang, David van Dijk, Janghoo Lim
Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population...
November 16, 2023: Neuron
https://read.qxmd.com/read/37863037/hd-and-sca1-tales-from-two-30-year-journeys-since-gene-discovery
#5
REVIEW
Leslie M Thompson, Harry T Orr
One of the more transformative findings in human genetics was the discovery that the expansion of unstable nucleotide repeats underlies a group of inherited neurological diseases. A subset of these unstable repeat neurodegenerative diseases is due to the expansion of a CAG trinucleotide repeat encoding a stretch of glutamines, i.e., the polyglutamine (polyQ) repeat neurodegenerative diseases. Among the CAG/polyQ repeat diseases are Huntington's disease (HD) and spinocerebellar ataxia type 1 (SCA1), in which the expansions are within widely expressed proteins...
October 12, 2023: Neuron
https://read.qxmd.com/read/37802886/dysregulation-of-alternative-splicing-in-spinocerebellar-ataxia-type-1
#6
JOURNAL ARTICLE
Victor Olmos, Evrett Thompson, Neha Gogia, Kimberly Luttik, Vaishnavi Veeranki, Luhan Ni, Serena Sim, Kelly Chen, Diane S Krause, Janghoo Lim
Spinocerebellar ataxia type 1 is caused by an expansion of the polyglutamine tract in ATAXIN-1. Ataxin-1 is broadly expressed throughout the brain and is involved in regulating gene expression. However, it is not yet known if mutant ataxin-1 can impact the regulation of alternative splicing events. We performed bulk RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that mutant ataxin-1 expression abnormally leads to diverse splicing events in the mouse cerebellum of spinocerebellar ataxia type 1...
October 6, 2023: Human Molecular Genetics
https://read.qxmd.com/read/37609676/bdnf-and-cerebellar-ataxia
#7
JOURNAL ARTICLE
Robert Lalonde, Magali Hernandez, Catherine Strazielle
Brain-derived neurotrophic factor (BDNF) has been proposed as a treatment for neurodegeneration, including diseases of the cerebellum, where BDNF levels or those of its main receptor, TrkB, are often diminished relative to controls, thereby serving as replacement therapy. Experimental evidence indicates that BDNF signaling countered cerebellar degeneration, sensorimotor deficits, or both, in transgenic ATXN1 mice mutated for ataxin-1, Cacna1a knock-in mice mutated for ataxin-6, mice injected with lentivectors encoding RNA sequences against human FXN into the cerebellar cortex, Kcnj6Wv (Weaver) mutant mice with granule cell degeneration, and rats with olivocerebellar transaction, similar to a BDNF-overexpressing transgenic line interbred with Cacng2stg mutant mice...
August 11, 2023: Current Drug Research Reviews
https://read.qxmd.com/read/37278528/spinocerebellar-ataxia-type-1-characteristics-in-patient-derived-fibroblast-and-ipsc-derived-neuronal-cultures
#8
JOURNAL ARTICLE
Ronald A M Buijsen, Michel Hu, Maria Sáez-González, Sofia Notopoulou, Eleni Mina, Winette Koning, Sarah L Gardiner, Linda M van der Graaf, Elena Daoutsali, Barry A Pepers, Hailiang Mei, Vera van Dis, Jean-Philippe Frimat, Arn M J M van den Maagdenberg, Spyros Petrakis, Willeke M C van Roon-Mom
BACKGROUND: Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein resulting in neuropathology including mutant ataxin-1 protein aggregation, aberrant neurodevelopment, and mitochondrial dysfunction. OBJECTIVES: Identify SCA1-relevant phenotypes in patient-specific fibroblasts and SCA1 induced pluripotent stem cells (iPSCs) neuronal cultures. METHODS: SCA1 iPSCs were generated and differentiated into neuronal cultures...
June 6, 2023: Movement Disorders: Official Journal of the Movement Disorder Society
https://read.qxmd.com/read/37238658/therapeutic-strategies-for-spinocerebellar-ataxia-type-1
#9
REVIEW
Laurie M C Kerkhof, Bart P C van de Warrenburg, Willeke M C van Roon-Mom, Ronald A M Buijsen
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the ATXN1 gene and is characterized mostly by a profound loss of cerebellar Purkinje cells, leading to disturbances in coordination, balance, and gait. At present, no curative treatment is available for SCA1. However, increasing knowledge on the cellular and molecular mechanisms of SCA1 has led the way towards several therapeutic strategies that can potentially slow disease progression...
May 2, 2023: Biomolecules
https://read.qxmd.com/read/36979479/mapk-is-a-mutual-pathway-targeted-by-anxiety-related-mirnas-and-e2f5-is-a-putative-target-for-anxiolytic-mirnas
#10
JOURNAL ARTICLE
Javad Amini, Cordian Beyer, Adib Zendedel, Nima Sanadgol
Anxiety-related disorders (ARDs) are chronic neuropsychological diseases and the sixth leading cause of disability in the world. As dysregulation of microRNAs (miRs) are observed in the pathological course of neuropsychiatric disorders, the present study aimed to introduce miRs that underlie anxiety processing in the brain. First, we collected the experimentally confirmed anxiety-related miRNAs (ARmiRs), predicted their target transcripts, and introduced critical cellular pathways with key commune hub genes...
March 16, 2023: Biomolecules
https://read.qxmd.com/read/36848492/on-the-identification-of-potential-novel-therapeutic-targets-for-spinocerebellar-ataxia-type-1-sca1-neurodegenerative-disease-using-evoppi3
#11
JOURNAL ARTICLE
André Sousa, Sara Rocha, Jorge Vieira, Miguel Reboiro-Jato, Hugo López-Fernández, Cristina P Vieira
EvoPPI (https://evoppi.i3s.up.pt), a meta-database for protein-protein interactions (PPI), has been upgraded (EvoPPI3) to accept new types of data, namely, PPI from patients, cell lines, and animal models, as well as data from gene modifier experiments, for nine neurodegenerative polyglutamine (polyQ) diseases caused by an abnormal expansion of the polyQ tract. The integration of the different types of data allows users to easily compare them, as here shown for Ataxin-1, the polyQ protein involved in spinocerebellar ataxia type 1 (SCA1) disease...
February 28, 2023: Journal of Integrative Bioinformatics
https://read.qxmd.com/read/36681886/ataxin-1-controls-the-expression-of-specific-non-coding-rnas-in-b-cells-upon-autoimmune-demyelination
#12
JOURNAL ARTICLE
Qin Ma, Alessandro Didonna
B cells play a key mechanistic role in the pathogenesis of multiple sclerosis (MS), a chronic neurological disease of the central nervous system with an autoimmune etiology. B cells contribute to disease initiation and progression by acting as professional antigen presenting cells as well as via secreting autoantibodies and pro-inflammatory cytokines. We have recently shown that the polyglutamine protein ataxin-1, which was first linked to the movement disorder spinocerebellar ataxia type 1 (SCA1), also acts as a master regulator of B cell functions in the context of CNS autoimmunity...
January 22, 2023: Immunology and Cell Biology
https://read.qxmd.com/read/36629882/elevation-of-hsa-mir-7-5p-level-mediated-by-ctbp1-p300-ap1-complex-targets-atxn1-to-trigger-nf-%C3%AE%C2%BAb-dependent-inflammation-response
#13
JOURNAL ARTICLE
Li-Qiong Lou, Wen-Qiang Zhou, Xin Song, Zhi Chen
Nuclear factor-κB (NF-κB)-mediated inflammation is a major cause of acute respiratory distress syndrome (ARDS). However, the regulatory mechanisms by which NF-κB transactivates proinflammatory cytokines remain unclear in the pathogenesis of ARDS. Herein, we report that the activating protein 1 (AP1) transcription factor recruits a histone acetyltransferase p300 and a transcriptional regulator C-terminal binding protein 1 (CtBP1) to assemble the CtBP1-p300-AP1 complex, which transactivates the expression of hsa-miR-7-5p in ARDS biopsies...
January 11, 2023: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://read.qxmd.com/read/36574355/cytosolic-stress-granules-relieve-the-ubiquitin-proteasome-system-in-the-nuclear-compartment
#14
JOURNAL ARTICLE
Shanshan Xu, Maria E Gierisch, Anna Katharina Schellhaus, Ina Poser, Simon Alberti, Florian A Salomons, Nico P Dantuma
The role of cytosolic stress granules in the integrated stress response has remained largely enigmatic. Here, we studied the functionality of the ubiquitin-proteasome system (UPS) in cells that were unable to form stress granules. Surprisingly, the inability of cells to form cytosolic stress granules had primarily a negative impact on the functionality of the nuclear UPS. While defective ribosome products (DRiPs) accumulated at stress granules in thermally stressed control cells, they localized to nucleoli in stress granule-deficient cells...
February 1, 2023: EMBO Journal
https://read.qxmd.com/read/36497172/targeting-mglu1-receptors-in-the-treatment-of-motor-and-cognitive-dysfunctions-in-mice-modeling-type-1-spinocerebellar-ataxia
#15
JOURNAL ARTICLE
Francesca Liberatore, Nico Antenucci, Daniel Tortolani, Giada Mascio, Federico Fanti, Manuel Sergi, Giuseppe Battaglia, Valeria Bruno, Ferdinando Nicoletti, Mauro Maccarrone, Serena Notartomaso
Type 1 spinocerebellar ataxia (SCA1) is a progressive neurodegenerative disorder with no effective treatment to date. Using mice modeling SCA1, it has been demonstrated that a drug that amplifies mGlu1 receptor activation (mGlu1 receptor PAM, Ro0711401) improves motor coordination without the development of tolerance when cerebellar dysfunction manifests (i.e., in 30-week-old heterozygous ataxin-1 [154Q/2Q] transgenic mice). SCA1 is also associated with cognitive dysfunction, which may precede cerebellar motor signs...
December 3, 2022: Cells
https://read.qxmd.com/read/36459834/generation-of-induced-pluripotent-stem-cell-ipsc-line-cjuhi001-a-derived-peripheral-blood-mononuclear-cells-of-spinocerebellar-ataxia-type-1-sca1-the-cag-repeat-mutation-in-atxn1-gene
#16
JOURNAL ARTICLE
Yinshi Jin, Guangxian Nan
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by CAG repeat mutations in the ATXN1 gene. In this study, we generated an induced pluripotent stem cell line (iPSC) by using non-integrating Sendai virus (SeV) from peripheral blood mononuclear cells(PBMCs)of SCA1 patient harboring a CAG repeat mutation in the ATXN1 gene. The induced patient-specific iPSC line with a normal karyotype and expresses pluripotent markers, it also shows differentiation totipotency and tridermogenesis in vitro...
November 14, 2022: Stem Cell Research
https://read.qxmd.com/read/36262042/towards-the-design-and-development-of-peptidomimetic-inhibitors-of-the-ataxin-1-aggregation-pathway
#17
JOURNAL ARTICLE
Marcello Miceli, Marco A Deriu, Gianvito Grasso
Spinocerebellar Ataxia Type 1 is a degenerative disorder caused by polyglutamine expansions and aggregation of Ataxin-1. The interaction between Capicua (CIC) and the AXH domain of Ataxin-1 protein has been suggested as a possible driver of aggregation for the expanded Ataxin-1 protein and the subsequent onset of Spinocerebellar ataxia 1. Experimental studies have demonstrated that short constructs of CIC may prevent such aggregation and suggested this as a possible candidate to inspire the rational design of peptidomimetics...
October 19, 2022: Biophysical Journal
https://read.qxmd.com/read/36208132/governing-dynamics-and-preferential-binding-of-the-axh-domain-influence-the-aggregation-pathway-of-ataxin-1
#18
JOURNAL ARTICLE
Vaishnavi Tammara, Atanu Das
The present state of understanding the mechanism of Spinocerebellar Ataxia-1, a fatal neurodegenerative disease linked to the protein Ataxin-1 (ATXN1), is baffled by a set of self-contradictory, and hence, inconclusive observations. This fallacy poses a bottleneck to the effective designing of curable drugs as the field is currently missing the specific druggable site. To understand the fundamentals of pathogenesis, we tried to decipher the intricacies of the extremely complicated landscape by targeting the relevant species that supposedly dictate the structure-function paradigm...
October 8, 2022: Proteins
https://read.qxmd.com/read/36078042/identifying-disease-signatures-in-the-spinocerebellar-ataxia-type-1-mouse-cortex
#19
JOURNAL ARTICLE
Kimberly Luttik, Victor Olmos, Ashley Owens, Aryaan Khan, Joy Yun, Terri Driessen, Janghoo Lim
The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is known to lead to the progressive degeneration of specific neuronal populations, including cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. The disease-causing protein ataxin-1 is fairly ubiquitously expressed throughout the brain and spinal cord, but most studies have primarily focused on the role of ataxin-1 in the cerebellum and brainstem. Therefore, the functions of ataxin-1 and the effects of SCA1 mutations in other brain regions including the cortex are not well-known...
August 24, 2022: Cells
https://read.qxmd.com/read/36054333/cic-missense-variants-contribute-to-susceptibility-for-spina-bifida
#20
JOURNAL ARTICLE
Xiao Han, Xuanye Cao, Vanessa Aguiar-Pulido, Wei Yang, Menuka Karki, Paula Andrea Pimienta Ramirez, Robert M Cabrera, Ying Linda Lin, Bogdan J Wlodarczyk, Gary M Shaw, M Elizabeth Ross, Cuilian Zhang, Richard H Finnell, Yunping Lei
Neural tube defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to the cerebral folate deficiency syndrome by downregulating folate receptor 1 (FOLR1) expression...
September 2, 2022: Human Mutation
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