Machado Joseph disease: clinical and genetic aspects, and current treatment

Saute, Jonas Alex Morales; Jardim, Laura Bannach

doi:10.1517/21678707.2015.1025747

Cited by 44 publications

(43 citation statements)

References 137 publications

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“…neurodegeneration | spinocerebellar ataxia | polyglutamine expansion | ataxin-3 | karyopherin S pinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), belongs to the group of neurodegenerative disorders characterized by a polyglutamine expansion in the expressed protein of the disease-associated gene (1). Within the general human population, the ATXN3 gene carries between 12 and 43 CAG repeats which are not associated with a phenotype, while patients carry between 51 and 91 repeats on the affected allele (2). The expansion in the protein leads to cellular dysfunction characterized by protein cleavage, mitochondrial dysfunction, autophagic disturbances, and protein aggregation (3).…”

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confidence: 99%

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

Sowa

Martin

Martins

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the 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,, and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in, 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, 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.

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confidence: 99%

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

Sowa

Martin

Martins

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The MJD, also known as spinocerebellar ataxia type 3, is caused by CSG expansions which codify a repetition of the amino acid glutamine in its correspondent protein 19 . It is a neurodegenerative dominant autosomal disease of late beginning, which involves predominantly the cerebellar, pyramidal, extrapyramidal, motor neurons and oculomotor systems.…”

Section: Discussionmentioning

confidence: 99%

“…Some studies about the MJD discuss that, although there is impact of dysphagia in the disease, it may not be associated with the period or with the progress of the other symptoms 5,19 . However, as it is a progressive disease, in which dysphagia may appear in it beginning, evaluating QOL is extremely important.…”

Section: Discussionmentioning

confidence: 99%

Qualidade de vida em pacientes com doença de Machado-Joseph sob acompanhamento fonoaudiológico para disfagia

2016

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The Machado-Joseph disease is a degenerative disease, currently considered the most frequent spinocerebellar ataxia. The degenerative process of the disease affects several regions and functions of the central and/or peripheral nervous system. The dysphagia is one of the symptoms of Machado-Joseph disease, being responsible for the clinical complications and for the aspiration pneumonia, its main cause of death. The goal of this paper is to verify the impact of the speech-language therapy in the quality of life of the Machado-Joseph disease patients. Four patients diagnosed with Machado-Joseph disease attended to the research, three female and one male, with age average in 46,5 years-old (± 18), and complaining about dysphagia. In the first session, all patients answered the protocol of quality of life in dysphagia assessment of Quality of Life in Dysphagia, SWAL -QOL were assessed for structural and functional aspects of swallowing and classified according to Functional Intake Scale for Oral (FOIS). After six speech therapy sessions conducted a new clinical evaluation of swallowing, again classified according to FOIS and answered the SWAL -QOL. Conclusions: After speech therapy, all patients showed better concept in the field fear of eating, food as a burden and fatigue, which can be inferred that there was an improvement in satisfaction with food processes and hence the quality of life accompanied subjects.

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“…Entrevistei pessoas diagnosticadas com a doença e alguns de seus familiares sem sintomas, mas com risco de serem portadores da condição genética que causa a enfermidade. A DMJ é a forma de ataxia hereditária mais comum no Brasil, tem expressão tardia e é autossômica dominante 5,6 . Entre os sintomas estão a desarticulação da fala, desequilíbrio da marcha, paralisia de membros inferiores e superiores e dificuldades para deglutição.…”

Section: Metodologiaunclassified

Trajetórias Terapêuticas Familiares: doenças raras hereditárias como sofrimento de longa duração

Aureliano

2018

Ciênc. saúde coletiva

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Machado Joseph disease: clinical and genetic aspects, and current treatment

Cited by 44 publications

References 137 publications

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

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

Qualidade de vida em pacientes com doença de Machado-Joseph sob acompanhamento fonoaudiológico para disfagia

Trajetórias Terapêuticas Familiares: doenças raras hereditárias como sofrimento de longa duração

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