Characterization of the dominant inheritance mechanism of Episodic Ataxia type 2

Dorgans, Kevin; Salvi, Julie; Bertaso, Federica; Bernard, Ludivine; Lory, Philippe; Doussau, Frédéric; Mezghrani, Alexandre

doi:10.1016/j.nbd.2017.07.004

Cited by 11 publications

(7 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Abnormity of these channels can lead to a variety of disorders (Zamponi et al, ). Numerous studies have confirmed the engagement of VGCCs in age‐related disease, including Parkinson disease (Ca v 1.3) (Zamponi et al, ), ataxia (Ca v 2.1) (Dorgans et al, ), Alzheimer's disease (Ca v 3.1) (Rice et al, ). Despite this, whether and how VGCCs exert influence on osteoporosis remains controversial.…”

Section: Discussionmentioning

confidence: 94%

Ca_v1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

Fei

Zhang

et al. 2019

Aging Cell

View full text Add to dashboard Cite

Aims Age‐related bone mass loss is one of the most prevalent diseases that afflict the elderly population. The decline in the osteogenic differentiation capacity of bone marrow‐derived mesenchymal stem cells (BMMSCs) is regarded as one of the central mediators. Voltage‐gated Ca2+ channels (VGCCs) play an important role in the regulation of various cell biological functions, and disruption of VGCCs is associated with several age‐related cellular characteristics and systemic symptoms. However, whether and how VGCCs cause the decreased osteogenic differentiation abilities of BMMSCs have not been fully elucidated. Methods Voltage‐gated Ca2+ channels related genes were screened, and the candidate gene was determined in several aging models. Functional role of determined channel on osteogenic differentiation of BMMSCs was investigated through gain and loss of function experiments. Molecular mechanism was explored, and intervention experiments in vivo and in vitro were performed. Results We found that Cav1.2 was downregulated in these aging models, and downregulation of Cav1.2 in Zmpste24−/− BMMSCs contributed to compromised osteogenic capacity. Mechanistically, Cav1.2 regulated the osteogenesis of BMMSCs through canonical Wnt/β‐catenin pathway. Moreover, upregulating the activity of Cav1.2 mitigated osteoporosis symptom in Zmpste24−/− mice. Conclusion Impaired osteogenic differentiation of Zmpste24−/− BMMSCs can be partly attributed to the decreased Cav1.2 expression, which leads to the inhibition of canonical Wnt pathway. Bay K8644 treatment could be an applicable approach for treating age‐related bone loss by ameliorating compromised osteogenic differentiation capacity through targeting Cav1.2 channel.

show abstract

Section: Discussionmentioning

confidence: 94%

Ca_v1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

Fei

Zhang

et al. 2019

Aging Cell

View full text Add to dashboard Cite

show abstract

“…It is well known that precision of PC pacemaking activity is essential for normal cerebellar functions and any impairment of PC intrinsic excitability leads to ataxic behaviors [54]. In several rodent models of ataxia, PCs are characterized by a lower rate of spontaneous ring compared to WT and/or by an irregular ring pattern [54,62,[74][75][76]. Here, we show that PCs in SCA7 mice re with a higher regularity in lobules VI and IX/X and a lower frequency in lobule VI, compared to WT littermates.…”

Section: Discussionmentioning

confidence: 99%

SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2

et al. 2021

View full text Add to dashboard Cite

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination and visual impairment due to progressive cerebellar and retinal degeneration.Alteration of other nervous tissues also contributes to symptoms. The mechanisms underlying motor incoordination of SCA7 remain to be characterized. SCA7 is caused by a polyglutamine (polyQ) expansion in ATXN7, a member of the transcriptional coactivator SAGA complex, which harbors histone modi cation activities. PolyQ expansion in other proteins is responsible for 5 other SCAs (SCA1-3, 6 and 17). However, the converging and diverging pathophysiological points remain poorly understood. Using a new SCA7 knock-in model carrying 140 glutamines in ATXN7, we analyzed cell-type speci c gene expression in the cerebellum. We show that gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks histone H3 acetylation and H2B ubiquitination. Our results further show that Purkinje cells (PCs) are far the most affected neurons: unlike other cerebellar cell types, PCs show reduced expression of 83 cell-type identity genes, critical for their spontaneous ring activity and synaptic functions. PC gene downregulation precedes morphological alterations, pacemaker dysfunction and motor incoordination. Strikingly, most PC identity genes downregulated in SCA7 mice are also decreased in early symptomatic SCA1 and SCA2 mice, revealing a common signature of early PC pathology involving cGMP-PKG and phosphatidylinositol signaling pathways and long-term depression. Our study thus points out molecular targets for therapeutic development which may prove bene cial for several SCAs. Finally, we show that unlike previous SCA7 mouse models, SCA7 140Q/5Q mice exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology and photoreceptor dystrophy, which account for progressive impairment of behavior, motor and vision functions. Therefore, SCA7 140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis.Page 5/52 [42]. While SCA proteins do not share any domain and have different cellular functions, changes in gene expression are central features in most polyQ SCAs. Therefore, the comparison of differentially expressed genes should provide insight into converging disease mechanisms.To get insight into the mechanisms underlying motor incoordination and cerebellar degeneration, we used a new SCA7 knock-in mice line carrying 140 CAG repeats. A comprehensive and longitudinal characterization of this model using a battery of analyses (motor and behavioral tests, retina imaging, MRI, electrophysiology, neuropathology) indicates that SCA7140Q/5Q mice remarkably recapitulate the major clinical features observed in patients, including cerebellar damage, speci c cerebral atrophy, peripheral nerves pathology and photoreceptor dystrophy, which account for prog...

show abstract

“…It is well known that precision of PC pacemaking activity is essential for normal cerebellar functions and any impairment of PC intrinsic excitability leads to ataxic behaviors (40). In several rodent models of ataxia, PCs are characterized by a lower rate of spontaneous ring compared to WT and/or by an irregular ring pattern (40,48,(63)(64)(65). Here, we show that in SCA7 mice at 38 weeks, PCs re with a higher regularity in lobules VI and IX/X and a lower frequency in lobule VI, compared to WT littermates.…”

Section: Discussionmentioning

confidence: 99%

SCA7 mice recapitulate CNS, PNS and retina pathologies and show a transcriptional signature of Purkinje cell dysfunction prevailing in SCA1 and SCA2 mice.

Niewiadomska-Cimicka¹,

Doussau²,

Pérot³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Background: Spinocerebellar ataxia type 7 (SCA7) is primarily characterized by progressive cerebellar degeneration with major alteration of Purkinje cells (PC) due to polyglutamine expansion in ATXN7, a subunit of SAGA transcriptional co-regulator complex. Additional neural tissues are affected and contribute to diverse symptoms. Current animal models were insufficient to recapitulate the broad spectrum of SCA7 pathology and the mechanisms of PC degeneration remain poorly explored. Methods: To delineate spatio-temporal features of SCA7, we performed a longitudinal characterization of a new knock-in mice line expressing ATXN7 with 140 glutamines (SCA7 140Q/5Q ) using a battery of analyses including motor tests, brain and retina imaging, morphometry, electrophysiology, electron microscopy and immunohistochemistry of disease tissues. We also determined the cerebellar transcriptome and cell-type specific gene deregulation. Results: Here we describe the first SCA7 knock-in mice that combine most cardinal features of SCA7, including retinal, cerebellar, cerebral and peripheral nerves pathologies, which account for progressive impairment of behavior, motor and vision functions. MRI and brain morphometry reveal atrophy of grey and white matter of specific cerebral regions, while peripheral nerves and photoreceptors show functional and morphological alterations. We show that cerebellar pathology is characterized by gene deregulation in all cerebellar cell types and alterations of SAGA-dependent epigenetic marks. Intranuclear accumulation of mutant ATXN7 and gene downregulation precede the onset of PC pacemaker dysfunction. Interestingly, PC show loss of expression of 83 PC-specific genes coding for ion channels, receptors and signaling proteins involved in pacemaker function and long-term depression, which are causal factors of many type of ataxias. Comparison of cerebellar transcriptome with other SCAs reveals a subset of 67 PC-specific genes downregulated in SCA1, SCA2 and SCA7, providing a common signature of early PC dysfunction. Conclusions: The SCA7 140Q/5Q mice represent a promising model for the investigation of different aspects of SCA7 pathogenesis, and offers opportunities for translational development of therapeutic strategies by targeting the brain, retina, peripheral nerve or whole body. Our results also provide insight into converging mechanisms of PC degeneration in polyglutamine SCAs and point out molecular targets for therapeutic development w hich may prove beneficial for several SCAs.

show abstract

Characterization of the dominant inheritance mechanism of Episodic Ataxia type 2

Cited by 11 publications

References 56 publications

Ca_v1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

Ca_v1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2

SCA7 mice recapitulate CNS, PNS and retina pathologies and show a transcriptional signature of Purkinje cell dysfunction prevailing in SCA1 and SCA2 mice.

Contact Info

Product

Resources

About

Characterization of the dominant inheritance mechanism of Episodic Ataxia type 2

Cited by 11 publications

References 56 publications

Cav1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

Cav1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2

SCA7 mice recapitulate CNS, PNS and retina pathologies and show a transcriptional signature of Purkinje cell dysfunction prevailing in SCA1 and SCA2 mice.

Contact Info

Product

Resources

About

Ca_v1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

Ca_v1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis