scholarly journals Cerebellar developmental deficits underlie neurodegenerative disorder spinocerebellar ataxia type 23

2020 ◽  
Author(s):  
Cleo JLM Smeets ◽  
Kai Y Ma ◽  
Simon E Fisher ◽  
Dineke S Verbeek
Keyword(s):  
Spinocerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Protein A ◽  
Spinocerebellar Ataxia Type ◽  
Gabaergic Interneuron ◽  
Altered Expression ◽  
Developmental Abnormalities ◽  
Limb Ataxia ◽  
Gabaergic Synapses

Abstract Background Spinocerebellar ataxia type 23 (SCA23) is a late-onset neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, for which there is no therapy available. It is caused by mutations in PDYN, which encodes the opioid precursor protein prodynorphin (PDYN). PDYN is processed into the opioid peptides α-neoendorphin, and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signalling, stress-induced responses, and addiction. Mutations causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYNR212W mice express human PDYN containing the SCA23 p.R212W mutation. These mice show gait deficits and progressive loss of motor function from 3 months of age. The cerebella of PDYNR212W mice show climbing fibre (CF) deficits from 3 months of age and Purkinje cell (PC) loss from 12 months of age. A mouse model for SCA1 showed similar CF deficits, and a recent study found additional developmental abnormalities, namely hyperproliferation of stem cells leading to increased GABAergic interneuron connectivity and non-cell autonomous disruption of PC function. As SCA23 mice show a similar pathology to SCA1 mice in adulthood, we hypothesized that SCA23 may also follow SCA1 pathology during development. Methods In the present study, we examined the cerebella of PDYNR212W mice during cerebellar development, from 2 to 8 weeks of age, using immunohistochemistry, protein, and RNA analysis. Results We uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma in PDYNR212W mice, possibly leading to the observed delay in early phase CF elimination between 2 and 3 weeks of age. Furthermore, CFs did not reach terminal height leaving proximal PC dendrites open to be occupied by parallel fibres (PFs). The observed increase in vGlut1 protein -a marker for PF-PC synapses- indicates that PFs indeed take over CF territory and have increased connectivity with PCs. Additionally, we detected altered expression of several critical Ca2+ channel subunits, potentially contributing to altered Ca2+ transients in PDYNR212W cerebella. Conclusions These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum.

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.

scholarly journals Spinocerebellar ataxia type 6 in Brazil

2008 ◽  
Vol 66 (3b) ◽  
pp. 691-694 ◽  
Author(s):  
Hélio A.G. Teive ◽  
Renato Puppi Munhoz ◽  
Salmo Raskin ◽  
Lineu César Werneck
Keyword(s):  
Cerebellar Ataxia ◽  
Spinocerebellar Ataxia ◽  
Late Onset ◽  
Cag Repeat ◽  
Autosomal Dominant Cerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 6 ◽  
Voltage Dependent ◽  
Pure Cerebellar Ataxia ◽  
Japanese Ancestry

Spinocerebellar ataxia type 6 (SCA 6) is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion in the SCA6 gene, a alpha 1A voltage-dependent calcium channel subunit gene on chromosome 19p13. SCA-6 is characterized predominantly by slowly progressive pure cerebellar ataxia with late onset. We report three index patients, with pure, late onset, cerebellar ataxia, belonging to three different Brazilian families, all of them with Japanese ancestry, from Hokkaido island of Japan.

scholarly journals Prodynorphin Mutations Cause the Neurodegenerative Disorder Spinocerebellar Ataxia Type 23

2010 ◽  
Vol 87 (5) ◽  
pp. 736 ◽  
Author(s):  
Georgy Bakalkin ◽  
Hiroyuki Watanabe ◽  
Justyna Jezierska ◽  
Cloë Depoorter ◽  
Corien Verschuuren-Bemelmans ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Spinocerebellar Ataxia Type

scholarly journals Altered retinal structure and function in Spinocerebellar ataxia type 3

2022 ◽  
Author(s):  
Vasileios Toulis ◽  
Ricardo Casaroli-Marano ◽  
Anna Camos-Carreras ◽  
Marc Figueras-Roca ◽  
Bernardo Sanchez-Dalmau ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Spinocerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Retinal Pigment ◽  
Structure And Function ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Retinal Structure ◽  
And Function ◽  
Type 3

Spinocerebellar ataxia type 3 is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine (polyQ)-encoding CAG repeat in the ATXN3 gene. Because the ATXN3 protein regulates photoreceptor ciliogenesis and phagocytosis, we aimed to explore whether expanded polyQ ATXN3 impacts retinal function and integrity in SCA3 patients and transgenic mice. We evaluated the retinal structure and function in five patients with Spinocerebellar ataxia type 3 and in a transgenic mouse model of this disease (YACMJD84.2, Q84) using, respectively, optical coherence tomography (OCT) and electroretinogram (ERG). We further determined in the transgenic mice: a) the retinal expression pattern of ATXN3 and assessed the distribution of cones and rods by immunofluorescence (IF); and b) the retinal ultrastructure by transmission electron microscopy (TEM). Some patients with Spinocerebellar ataxia type 3 in our cohort revealed: i) reduced central macular thickness indirectly correlated with disease duration; ii) decreased thickness of the macula and the ganglion cell layer, and reduced macula volume inversely correlated with disease severity (SARA score); and iii) electrophysiological dysfunction of cones, rods, and inner retinal cells. Transgenic mice replicated the human OCT and ERG findings with aged homozygous Q84/Q84 mice showing a stronger phenotype accompanied by further thinning of the outer nuclear layer and photoreceptor layer and highly reduced cone and rod activities, thus supporting severe retinal dysfunction in these mice. In addition, Q84 mice showed progressive accumulation of ATXN3-positive aggregates throughout several retinal layers and depletion of cones alongside the disease course. TEM analysis of aged Q84/Q84 mouse retinas supported the IF ATXN3 aggregation findings by revealing the presence of high number of negative electron dense puncta in ganglion cells, inner plexiform and inner nuclear layers, and further showed thinning of the outer plexiform layer, thickening of the retinal pigment epithelium and elongation of apical microvilli. Our results indicate that retinal alterations detected by non-invasive eye examination using OCT and ERG could represent a biological marker of disease progression and severity in patients with Spinocerebellar ataxia type 3.

scholarly journals Karyopherin α-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3

2018 ◽  
Vol 115 (11) ◽  
pp. E2624-E2633 ◽  
Author(s):  
Anna Sergeevna Sowa ◽  
Elodie Martin ◽  
Inês Morgado Martins ◽  
Jana Schmidt ◽  
Reinhard Depping ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Nuclear Localization ◽  
Neurodegenerative Disorder ◽  
Nucleocytoplasmic Transport ◽  
Spinocerebellar Ataxia Type ◽  
Nuclear Pore ◽  
Spinocerebellar Ataxia Type 3 ◽  
Nuclear Localization Signals ◽  
Positive Effects ◽  
Type 3

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, Drosophila, and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective Drosophila orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in Drosophila, KPNA3/Kap-α3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, KPNA3 knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), this work unites ataxin-3 structure to the nuclear pore machinery and provides a link between karyopherins, NLS signals, and polyglutamine disease, as well as demonstrates that KPNA3 is a key player in the pathogenesis of SCA3.

scholarly journals Development of a Multiplex Ligation-Dependent Probe Amplification Assay for Diagnosis and Estimation of the Frequency of Spinocerebellar Ataxia Type 15

2009 ◽  
Vol 55 (7) ◽  
pp. 1415-1418 ◽  
Author(s):  
Devika Ganesamoorthy ◽  
Damien L Bruno ◽  
Jacqueline Schoumans ◽  
Elsdon Storey ◽  
Martin B Delatycki ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Cost Effective ◽  
Proximal Region ◽  
Spinocerebellar Ataxia Type ◽  
Molecular Defect ◽  
Neighboring Gene ◽  
New Family ◽  
Amplification Assay ◽  
Dependent Probe

Abstract Background: Spinocerebellar ataxia type 15 (SCA15) is a slowly progressive neurodegenerative disorder characterized by cerebellar ataxia. Mutation of the ITPR1 gene (inositol 1,4,5-triphosphate receptor, type 1) has been identified recently as the underlying cause, and in most cases the molecular defect is a multiexon deletion. To date, 5 different SCA15 families have been identified with ITPR1 gene deletion. Methods: We have designed a synthetic, dual-color multiplex ligation-dependent probe amplification (MLPA) assay that measures copy number with high precision in selected exons across the entire length of ITPR1 and the proximal region of the neighboring gene, SUMF1 (sulfatase modifying factor 1). We screened 189 idiopathic ataxic patients with this MLPA assay. Results: We identified ITPR1 deletion of exons 1–10 in the previously reported AUS1 family (4 members) and deletion of exons 1–38 in a new family (2 members). In addition to the multiexon deletions, apparent single-exon deletions identified in 2 other patients were subsequently shown to be due to single-nucleotide changes at the ligation sites. Conclusions: The frequency of ITPR1 deletions is 2.7% in known familial cases. This finding suggests that SCA15 is one of the “less common” SCAs. Although the deletions in the 5 families identified worldwide thus far have been of differing sizes, all share deletion of exons 1–10. This region may be important, both in terms of the underlying pathogenetic mechanism and as a pragmatic target for an accurate, robust, and cost-effective diagnostic analysis.

scholarly journals Late-onset oro-facial dyskinesia in Spinocerebellar Ataxia type 2: a case report

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Floriana Giardina ◽  
Giuseppe Lanza ◽  
Francesco Calì ◽  
Raffaele Ferri
Keyword(s):  
Case Report ◽  
Spinocerebellar Ataxia ◽  
Late Onset ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 2 ◽  
Facial Dyskinesia

scholarly journals Spinocerebellar Ataxia Type 1 protein Ataxin-1 is signalled to DNA damage by Ataxia Telangiectasia Mutated kinase

2019 ◽  
Author(s):  
Celeste E. Suart ◽  
Alma M. Perez ◽  
Ismael Al-Ramahi ◽  
Tamara Maiuri ◽  
Juan Botas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Spinocerebellar Ataxia ◽  
Ataxia Telangiectasia ◽  
Neurodegenerative Disorder ◽  
Age At Onset ◽  
Spinocerebellar Ataxia Type ◽  
Ataxia Telangiectasia Mutated ◽  
Spinocerebellar Ataxia Type 1 ◽  
Polyglutamine Expansion

ABSTRACTSpinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-1 protein. Recent genetic correlational studies have implicated DNA damage repair pathways in modifying the age at onset of disease symptoms in SCA1 and Huntington’s Disease, another polyglutamine expansion disease. We demonstrate that both endogenous and transfected ataxin-1 localizes to sites of DNA damage, which is impaired by polyglutamine expansion. This response is dependent on ataxia telangiectasia mutated (ATM) kinase activity. Further, we characterize an ATM phosphorylation motif within ataxin-1 at serine 188. We show reduction of the Drosophila ATM homolog levels in a ATXN1[82Q] Drosophila model through shRNA or genetic cross ameliorates motor symptoms. These findings offer a possible explanation as to why DNA repair was implicated in SCA1 pathogenesis by past studies. The similarities between the ataxin-1 and the huntingtin responses to DNA damage provide further support for a shared pathogenic mechanism for polyglutamine expansion diseases.

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