Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model

Ortiz, Judit M. Pérez; Mollema, Nissa; Toker, Nicholas; Adamski, Carolyn J.; O’Callaghan, Brennon; Duvick, Lisa A.; Friedrich, Jillian; Walters, Michael A.; Strasser, Jessica M.; Hawkinson, Jon E.; Zoghbi, Huda Y.; Henzler, Christine; Orr, Harry T.; Lagalwar, Sarita

doi:10.1016/j.nbd.2018.05.002

Cited by 29 publications

(13 citation statements)

References 51 publications

(80 reference statements)

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“…Spinocerebellar ataxia type 1 is an inherited neurodegenerative disease associated with a gain‐of‐function mutation in ataxin‐1 that contributes to cerebellar and brain stem degeneration. Recently, mechanistic studies have validated the importance of ATXN1‐CIC complexes in the pathophysiology of the neurodegenerative disease 46,47 and highlighted the importance of ataxin‐1 in neuronal maintenance. Atxn1 (mouse homolog) is expressed in mouse cochlear inner and outer hair cells as identified in the Gene Expression Analysis Resource (gEAR) database 48 …”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic risk factors for radiation‐associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort

Trendowski

Baedke

Sapkota

et al. 2021

Cancer

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BACKGROUND Cranial radiation therapy (CRT) is associated with ototoxicity, which manifests as hearing loss and tinnitus. The authors sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with CRT. METHODS Logistic regression evaluated associations of tinnitus (n = 1991) and hearing loss (n = 2198) with nongenetic risk factors and comorbidities among CRT‐treated survivors in the Childhood Cancer Survivor Study. Genome‐wide association studies (GWASs) of CRT‐related tinnitus and hearing loss were also performed. RESULTS Males were more likely to report CRT‐related tinnitus (9.4% vs 5.4%; P = 5.1 × 10−4) and hearing loss (14.0% vs 10.7%; P = .02) than females. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: P < 2 × 10−16; hearing loss: P = 6.4 × 10−9), take antidepressants (tinnitus: P = .02; hearing loss: P = .01), and report poorer overall health (tinnitus: P = 1.5 × 10−6; hearing loss: P = 1.7 × 10−6) in comparison with controls. GWAS of CRT‐related tinnitus revealed a genome‐wide significant signal in chromosome 1 led by rs203248 (P = 1.5 × 10−9), whereas GWAS of CRT‐related hearing loss identified rs332013 (P = 5.8 × 10−7) in chromosome 8 and rs67522722 (P = 7.8 × 10−7) in chromosome 6 as nearly genome‐wide significant. A replication analysis identified rs67522722, intronic to ATXN1, as being significantly associated with CRT‐related hearing loss (P = .03) and de novo hearing loss (P = 3.6 × 10−4). CONCLUSIONS CRT‐associated ototoxicity was associated with sex, several neuro‐otological symptoms, increased antidepressant use, and poorer self‐reported health. GWAS of CRT‐related hearing loss identified rs67522722, which was supported in an independent cohort of survivors. LAY SUMMARY Hearing loss and subjective tinnitus (the perception of noise or ringing in the ear) are long‐term side effects of cancer treatment and are common in children treated with radiation to the brain. These toxicities can affect childhood development and potentially contribute to serious learning and behavioral difficulties. This study's data indicate that males are at greater risk for hearing loss and tinnitus than females after radiation therapy to the brain. Those who develop these toxicities are more likely to use antidepressants and report poorer overall health. Health care providers can improve the management of survivors by informing patients and/or their parents of these risks.

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Section: Discussionmentioning

confidence: 99%

Clinical and genetic risk factors for radiation‐associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort

Trendowski

Baedke

Sapkota

et al. 2021

Cancer

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“…1B). Previous research [16,[18][19][20][21][22] identi ed a second molecular attribute, phosphorylation of the ATXN1 Serine 776 site, that promotes aggregate formation speci cally through 14-3-3 stabilization. Expression of phospho-resistant ATXN1[82Q-A776], in which the Serine 776 is mutated to an Alanine, is diffuse throughout the cytoplasm and nucleus (Fig.…”

Section: Atxn1[82q] Aggregate Formation In Daoy Cellsmentioning

confidence: 99%

Intercellular Propagation and Aggregate Seeding of Mutant Ataxin-1

Huang

Toker

Burr

et al. 2021

Preprint

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Intercellular propagation of aggregated protein inclusions along actin-based tunneling nanotubes (TNTs) has been reported as a means of pathogenic spread in Alzheimer’s, Parkinson’s and Huntington’s Disease. Propagation of oligomeric-structured polyglutamine-expanded ataxin-1 (Atxn1[154Q]) has been reported in the cerebellum of a Spinocerebellar ataxia type 1 (SCA1) knock-in mouse to correlate with disease propagation. In this study, we investigated whether a physiologically-relevant polyglutamine-expanded ATXN1 protein (ATXN1[82Q]) could propagate intercellularly. Using a cerebellar-derived live cell model, we observed ATXN1 aggregates form in the nucleus, export out of the nucleus into the cytoplasm, and finally, propagate to neighboring cells along actin-based intercellular connections. Additionally, we observed the facilitation of aggregate-resistant proteins into aggregates given the presence of aggregation-prone proteins within a cell. Taken together, our results support a pathogenic role of intercellular propagation of polyglutamine-expanded ATXN1 inclusions.

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“…For instance, sulforaphane can up-regulate the expression of all proteasome subunit genes through activation of the transcription factors Nrf1 and Nrf2 [80,81]. In addition, all of the following inhibitors: inhibitor of ubiquitin-specific protease 14 (IU1), an inhibitor of Protein kinase A (S776), GSK690693, S100B inhibitor (TRTK12) and a synthetic molecule (JMF1907), suppressed the formation of polyQ protein intranuclear inclusions in SCA models [79,[82][83][84]. [60] Recent advances in elucidating the molecular basis that underlies polyQ SCAs have boosted the design of therapeutic strategies against these disorders [61].…”

Section: Scamentioning

confidence: 99%

New Perspectives of Gene Therapy on Polyglutamine Spinocerebellar Ataxias: From Molecular Targets to Novel Nanovectors

et al. 2021

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Seven of the most frequent spinocerebellar ataxias (SCAs) are caused by a pathological expansion of a cytosine, adenine and guanine (CAG) trinucleotide repeat located in exonic regions of unrelated genes, which in turn leads to the synthesis of polyglutamine (polyQ) proteins. PolyQ proteins are prone to aggregate and form intracellular inclusions, which alter diverse cellular pathways, including transcriptional regulation, protein clearance, calcium homeostasis and apoptosis, ultimately leading to neurodegeneration. At present, treatment for SCAs is limited to symptomatic intervention, and there is no therapeutic approach to prevent or reverse disease progression. This review provides a compilation of the experimental advances obtained in cell-based and animal models toward the development of gene therapy strategies against polyQ SCAs, providing a discussion of their potential application in clinical trials. In the second part, we describe the promising potential of nanotechnology developments to treat polyQ SCA diseases. We describe, in detail, how the design of nanoparticle (NP) systems with different physicochemical and functionalization characteristics has been approached, in order to determine their ability to evade the immune system response and to enhance brain delivery of molecular tools. In the final part of this review, the imminent application of NP-based strategies in clinical trials for the treatment of polyQ SCA diseases is discussed.

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Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model

Cited by 29 publications

References 51 publications

Clinical and genetic risk factors for radiation‐associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort

Clinical and genetic risk factors for radiation‐associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort

Intercellular Propagation and Aggregate Seeding of Mutant Ataxin-1

New Perspectives of Gene Therapy on Polyglutamine Spinocerebellar Ataxias: From Molecular Targets to Novel Nanovectors

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