Insights into the molecular basis of polyglutamine neurodegeneration from studies of a spinocerebellar ataxia type 7 mouse model

2003 ◽  
Vol 100 (1-4) ◽  
pp. 164-174 ◽  
Author(s):  
S.K. Grote ◽  
A.R. La Spada
Keyword(s):  
Mouse Model ◽  
Spinocerebellar Ataxia ◽  
Molecular Basis ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7

scholarly journals Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model

2013 ◽  
Vol 8 (1) ◽  
pp. 42 ◽  
Author(s):  
Carlotta E Duncan ◽  
Mahru C An ◽  
Theodora Papanikolaou ◽  
Caitlin Rugani ◽  
Cathy Vitelli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Histone Deacetylase ◽  
Spinocerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Histone Deacetylase 3 ◽  
Spinocerebellar Ataxia Type 7

scholarly journals Phrenic and Hypoglossal motor unit pathology in a Spinocerebellar ataxia type 7 mouse model

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Debolina Biswas ◽  
Justin Dhindsa ◽  
Laura Strickland ◽  
Logan Pucci ◽  
Mai ElMallah
Keyword(s):  
Mouse Model ◽  
Motor Unit ◽  
Spinocerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7

scholarly journals Respiratory dysfunction in a mouse model of spinocerebellar ataxia type 7

2021 ◽  
Author(s):  
Anna F. Fusco ◽  
Logan A. Pucci ◽  
Pawel M. Switonski ◽  
Debolina D. Biswas ◽  
Angela L. McCall ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Mouse Model ◽  
Spinocerebellar Ataxia ◽  
Motor Neurons ◽  
Upper Airway ◽  
Cag Repeats ◽  
Whole Body ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7 ◽  
Respiratory Challenge

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the ataxin-7 gene. Infantile-onset SCA7 patients display extremely large repeat expansions (>200 CAGs) and exhibit progressive ataxia, dysarthria, dysphagia and retinal degeneration. Severe hypotonia, aspiration pneumonia and respiratory failure often contribute to death in affected infants. To better understand the features of respiratory and upper airway dysfunction in SCA7, we examined breathing and putative phrenic and hypoglossal neuropathology in a knock-in mouse model of early-onset SCA7 carrying an expanded allele with 266 CAG repeats. Whole-body plethysmography was used to measure awake, spontaneous breathing at baseline in normoxia and during a hypercapnic/hypoxic respiratory challenge at 4 and 8 weeks, before and after onset of disease. Postmortem studies included quantification of putative phrenic and hypoglossal motor neurons and microglia and analysis of ataxin-7 aggregation at end stage. SCA7-266Q mice have profound breathing deficits during a respiratory challenge, exhibiting reduced respiratory output and a greater percentage of time in apnea. Histologically, putative phrenic and hypoglossal motor neurons of SCA7 mice exhibit a reduction in number accompanied by increased microglial activation, indicating neurodegeneration and neuroinflammation. Furthermore, intranuclear ataxin-7 accumulation is observed in cells neighboring putative phrenic and hypoglossal motor neurons in SCA7 mice. These findings reveal the importance of phrenic and hypoglossal motor neuron pathology associated with respiratory failure and upper airway dysfunction, which are observed in infantile-onset SCA7 patients and likely contribute to their early death.

scholarly journals In vivo assessment of neurodegeneration in Spinocerebellar Ataxia type 7

2021 ◽  
Vol 29 ◽  
pp. 102561
Author(s):  
Jacob A. Parker ◽  
Shabbir H. Merchant ◽  
Sanaz Attaripour-Isfahani ◽  
Hyun Joo Cho ◽  
Patrick McGurrin ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7 ◽  
In Vivo Assessment

Cervical Spinal Cord Degeneration in Spinocerebellar Ataxia Type 7

2021 ◽  
Author(s):  
C.R. Hernandez-Castillo ◽  
R. Diaz ◽  
T.J.R. Rezende ◽  
I. Adanyeguh ◽  
I.H. Harding ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinocerebellar Ataxia ◽  
Cervical Spinal Cord ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7

scholarly journals Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7

2018 ◽  
Vol 10 (465) ◽  
pp. eaap8677 ◽  
Author(s):  
Chenchen Niu ◽  
Thazah P. Prakash ◽  
Aneeza Kim ◽  
John L. Quach ◽  
Laryssa A. Huryn ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Spinocerebellar Ataxia ◽  
Visual Function ◽  
Antisense Oligonucleotides ◽  
Neurodegenerative Disorder ◽  
Retinal Disease ◽  
Fundus Photography ◽  
Spinocerebellar Ataxia Type ◽  
Autofluorescence Imaging ◽  
Spinocerebellar Ataxia Type 7

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar and retinal degeneration, and is caused by a CAG-polyglutamine repeat expansion in the ATAXIN-7 gene. Patients with SCA7 develop progressive cone-rod dystrophy, typically resulting in blindness. Antisense oligonucleotides (ASOs) are single-stranded chemically modified nucleic acids designed to mediate the destruction, prevent the translation, or modify the processing of targeted RNAs. Here, we evaluated ASOs as treatments for SCA7 retinal degeneration in representative mouse models of the disease after injection into the vitreous humor of the eye. Using Ataxin-7 aggregation, visual function, retinal histopathology, gene expression, and epigenetic dysregulation as outcome measures, we found that ASO-mediated Ataxin-7 knockdown yielded improvements in treated SCA7 mice. In SCA7 mice with retinal disease, intravitreal injection of Ataxin-7 ASOs also improved visual function despite initiating treatment after symptom onset. Using color fundus photography and autofluorescence imaging, we also determined the nature of retinal degeneration in human SCA7 patients. We observed variable disease severity and cataloged rapidly progressive retinal degeneration. Given the accessibility of neural retina, availability of objective, quantitative readouts for monitoring therapeutic response, and the rapid disease progression in SCA7, ASOs targeting ATAXIN-7 might represent a viable treatment for SCA7 retinal degeneration.

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