Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

Egorova, Polina A.; Bezprozvanny, Ilya

doi:10.1007/s13311-019-00777-6

Cited by 36 publications

(23 citation statements)

References 231 publications

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“…mATXN2 accumulates in the cytoplasm and nucleus and forms aggregates in SCA2 (Seidel et al, 2017). ATXN2 is implicated in RNA metabolism including stability, translation, and degradation (Nonhoff et al, 2007;Egorova and Bezprozvanny, 2019). It contains an RNA binding Lsm domain functionally relevant to pre-mRNA splicing and mRNA decay (Ralser et al, 2005).…”

Section: Sca2mentioning

confidence: 99%

Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion

2020

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Polyglutamine spinocerebellar ataxias (polyQ SCAs) include SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 and constitute a group of adult onset neurodegenerative disorders caused by the expansion of a CAG repeat sequence located within the coding region of specific genes, which translates into polyglutamine tract in the corresponding proteins. PolyQ SCAs are characterized by degeneration of the cerebellum and its associated structures and lead to progressive ataxia and other diverse symptoms. In recent years, gene and epigenetic deregulations have been shown to play a critical role in the pathogenesis of polyQ SCAs. Here, we provide an overview of the functions of wild type and pathogenic polyQ SCA proteins in gene regulation, describe the extent and nature of gene expression changes and their pathological consequences in diseases, and discuss potential avenues to further investigate converging and distinct disease pathways and to develop therapeutic strategies.

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Section: Sca2mentioning

confidence: 99%

Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion

2020

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“…Probably the most comprehensive review of possible drug targets of patients with SCAs was performed by Lazlo et al in 2019 ( Szpisjak et al, 2019 ). The detailed review of the molecular targets and therapeutic strategies of each SCAs have recently been reviewed elsewhere ( Perez Ortiz and Orr, 2018 ; Egorova and Bezprozvanny, 2019 ; Ishikawa and Nagai, 2019 ; Niewiadomska-Cimicka and Trottier, 2019 ). Therefore, the objective of this section is to give a brief description of the main therapeutic options in terms of ophthalmic pathology in the most common polyQ SCAs (SCA1, 2, 3, 6, and 7).…”

Section: Therapeutic Strategies For Ophthalmic Abnormalitiesmentioning

confidence: 99%

Ophthalmic Manifestations and Genetics of the Polyglutamine Autosomal Dominant Spinocerebellar Ataxias: A Review

2020

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Spinocerebellar ataxia (SCA) is a part of the cerebellar neurodegenerative disease group that is diverse in genetics and phenotypes. It usually shows autosomal dominant inheritance. SCAs, always together with the cerebellar degeneration, may exhibit clinical deficits in brainstem or eye, especially retina or optic nerve. Interestingly, autosomal dominant SCAs share a common genetic mechanism; the length of the glutamine chain is abnormally expanded due to the increase in the cytosine-adenine-guanine (CAG) repeats of the disease causing gene. Studies have suggested that the mutant ataxin induces alteration of protein conformation and abnormal aggregation resulting in nuclear inclusions, and causes cellular loss of photoreceptors through a toxic effect. As a result, these pathologic changes induce a downregulation of genes involved in the phototransduction, development, and differentiation of photoreceptors such as CRX, one of the photoreceptor transcription factors. However, the exact mechanism of neuronal degeneration by mutant ataxin restricted to only certain type of neuronal cell including cerebellar Purkinje neurons and photoreceptor is still unclear. The most common SCAs are types 1, 2, 3, 6, 7, and 17 which contain about 80% of autosomal dominant SCA cases. Various aspects of eye movement abnormalities are evident depending on the degree of cerebellar and brainstem degeneration in SCAs. In addition, certain types of SCAs such as SCA7 are characterized by both cerebellar ataxia and visual loss mainly due to retinal degeneration. The severity of the retinopathy can vary from occult macular photoreceptor disruption to extensive retinal atrophy and is correlated with the number of CAG repeats. The value of using optical coherence tomography in conjunction with electrodiagnostic and genetic testing is emphasized as the combination of these tests can provide critical information regarding the etiology, morphological evaluation, and functional significances. Therefore, ophthalmologists need to recognize and differentiate SCAs in order to properly diagnose and evaluate the disease. In this review, we have described and discussed SCAs showing ophthalmic abnormalities with particular attention to their ophthalmic features, neurodegenerative mechanisms, genetics, and future perspectives.

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“…Meanwhile, the allosteric modulation of SK channels restores the precision of PCs pacemaking activity in different murine models of ataxia (Walter et al, 2006;Alvina and Khodakhah, 2010b;Shakkottai et al, 2011;Kasumu et al, 2012a;Egorova et al, 2016). We assume, that the pharmacological activation of SK channels enhances the hyperpolarization of the PC membrane and negatively modulates the activity of the voltage-dependent calcium channels thus causing the reduction of the calcium entry to the cytoplasm from the extracellular space (Egorova and Bezprozvanny, 2019).…”

Section: Chz As a Potential Treatment Of Ataxic Symptoms In Hdmentioning

confidence: 99%

“…The cerebellum controls the muscular functions and motor behavior. The cerebellar PCs represent the primary functioning unit in the cerebellum since their axons form the sole way out of the cerebellar cortex to the cerebellar nuclei and other deep brain areas (Egorova and Bezprozvanny, 2019). The cerebellar PCs intrinsically generate spikes at a stable frequency (Llinas and Sugimori, 1980;Nam and Hockberger, 1997;Bean, 1997, 1999;Womack and Khodakhah, 2002;Smith and Otis, 2003;De Zeeuw et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Ataxic Symptoms in Huntington’s Disease Transgenic Mouse Model Are Alleviated by Chlorzoxazone

2020

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Huntington's disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein, Striatum atrophy in HD leads to a progressive disturbance of psychiatric, motor, and cognitive function. Recent studies of HD patients revealed that the degeneration of cerebellum is also observed independently from the striatal atrophy during early HD stage and may contribute to the motor impairment and ataxia observed in HD. Cerebellar Purkinje cells (PCs) are responsible for the proper cerebellar pathways functioning and motor control. Recent studies on mouse models of HD have shown that the abnormality of the biochemical functions of PCs are observed in HD, suggesting the contribution of PC dysfunction and death to the impaired movement coordination observed in HD. To investigate ataxic symptoms in HD we performed a series of experiments with the yeast artificial chromosome transgenic mouse model of HD (YAC128). Using extracellular single-unit recording method we found that the portion of the cerebellar PCs with bursting and irregular patterns of spontaneous activity drastically rises in aged YAC128 HD mice when compared with wild type littermates. Previous studies demonstrated that SK channels are responsible for the cerebellar PC pacemaker activity and that positive modulation of SK channel activity exerted beneficial effects in different ataxic mouse models. Here we studied effects of the SK channels modulator chlorzoxazone (CHZ) on the motor behavior of YAC128 HD mice and also on the electrophysiological activity and neuroanatomy of the cerebellar PCs from these mice. We determined that the long-term intraperitoneal injections of CHZ alleviated the progressive impairment in the firing pattern of YAC128 PCs. We also demonstrated that treatment with CHZ rescued age-dependent motor incoordination and improved the cerebellar morphology in YAC128 mice. We propose that abnormal changes in the PC firing patterns might be a one of the possible causes of ataxic symptoms in HD and in other polyglutamine disorders and that the pharmacological activation of SK channels may serve as a potential way to improve the activity of cerebellar PCs and relieve the ataxic phenotype in HD patients.

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Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

Cited by 36 publications

References 231 publications

Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion

Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion

Ophthalmic Manifestations and Genetics of the Polyglutamine Autosomal Dominant Spinocerebellar Ataxias: A Review

Ataxic Symptoms in Huntington’s Disease Transgenic Mouse Model Are Alleviated by Chlorzoxazone

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