scholarly journals CAG repeat-binding small molecule improves motor coordination impairment in a mouse model of Dentatorubral–pallidoluysian atrophy

2022 ◽  
Vol 163 ◽  
pp. 105604
Author(s):  
Yuhei Hasuike ◽  
Hana Tanaka ◽  
Terence Gall-Duncan ◽  
Mustafa Mehkary ◽  
Kazuhiko Nakatani ◽  
...  
Author(s):  
Nicholas S Caron ◽  
Amber L Southwell ◽  
Cynthia C Brouwers ◽  
Louisa Dal Cengio ◽  
Yuanyun Xie ◽  
...  

AbstractHuntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.


2016 ◽  
Vol 12 (6) ◽  
pp. 444-451 ◽  
Author(s):  
Kumar N Alagramam ◽  
Suhasini R Gopal ◽  
Ruishuang Geng ◽  
Daniel H-C Chen ◽  
Ina Nemet ◽  
...  

PLoS ONE ◽  
2012 ◽  
Vol 7 (3) ◽  
pp. e33976 ◽  
Author(s):  
Robin M. Hallett ◽  
Maria K. Kondratyev ◽  
Andrew O. Giacomelli ◽  
Allison M. L. Nixon ◽  
Adele Girgis-Gabardo ◽  
...  

Author(s):  
Eva Haas ◽  
Rana D. Incebacak ◽  
Thomas Hentrich ◽  
Chrisovalantou Huridou ◽  
Thorsten Schmidt ◽  
...  

AbstractSpinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.


2020 ◽  
Vol 201 ◽  
pp. 108274
Author(s):  
Daniel K. Crawford ◽  
Phillip Vanlandingham ◽  
Susan Schneider ◽  
Matthew M. Goddeeris

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