Fibroblasts of Machado Joseph Disease patients reveal autophagy impairment

Onofre, Isabel; Mendonça, Nuno; Lopes, Sara; Nobre, Rui Jorge; Melo, Joana Barbosa; Carreira, Isabel M.; Januário, Cristina; Gonçalves, António Freire; Almeida, Luís Pereira de

doi:10.1038/srep28220

Cited by 72 publications

(67 citation statements)

References 45 publications

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“…Over the last years, our group has focused on the study of autophagy in MJD and has identified this pathway as a relevant contributor to the neuropathology. We showed that autophagy is impaired in human brain tissue and fibroblasts of MJD patients and also in different animal and cellular models of MJD [8][9][10][11]. Moreover, upon local lentiviral-mediated expression of the autophagic protein 6/beclin-1 (Atg6/beclin-1) in the brain, we observed an alleviation of neuropathological and behavioral defects of MJD mouse models, evidencing that autophagy activation is a promising strategy to block MJD progression [8,11].…”

Section: Introductionmentioning

confidence: 77%

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

et al. 2020

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Background: Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 aggregation and neuronal degeneration. There is no treatment available to block or delay disease progression. In this work we investigated whether trehalose, a natural occurring disaccharide widely used in food and cosmetic industry, would rescue biochemical, behavioral and neuropathological features of an in vitro and of a severe MJD transgenic mouse model. Methods: Two MJD animal models, a lentiviral based and a transgenic model, were orally treated with 2% trehalose solution for a period of 4 and 30 weeks, respectively. Motor behavior (rotarod, grip strength and footprint patterns) was evaluated at different time points and neuropathological features were evaluated upon in-life phase termination. Results: Trehalose-treated MJD mice equilibrated for a longer time in the rotarod apparatus and exhibited an improvement of ataxic gait in footprint analysis. Trehalose-mediated improvements in motor behaviour were associated with a reduction of the MJD-associated neuropathology, as MJD transgenic mice treated with trehalose presented preservation of cerebellar layers thickness and a decrease in the size of ataxin-3 aggregates in Purkinje cells. In agreement, an improvement of neuropathological features was also observed in the full length lentiviral-based mouse model of MJD submitted to 2% trehalose treatment. Conclusions: The present study suggests trehalose as a safety pharmacological strategy to counteract MJD-associated behavioural and neuropathological impairments.

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Section: Introductionmentioning

confidence: 77%

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

et al. 2020

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“…Autophagy has been linked to neurodegeneration [ 58 ]. Both of SCA 3 fibroblast and SCA 7 mouth model demonstrate impaired autophagy [ 59 , 60 ]. A mammalian target of rapamycin (mTOR) inhibitor that upregulates autophagy clears ataxin-3 and aggregates in brain in a SCA 3 mouse model.…”

Section: Advances In Molecular Diagnoses and Disease Mechanismsmentioning

confidence: 99%

Spinocerebellar ataxia: an update

et al. 2018

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Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative ataxic disorders with autosomal dominant inheritance. We aim to provide an update on the recent clinical and scientific progresses in SCA where numerous novel genes have been identified with next-generation sequencing techniques. The main disease mechanisms of these SCAs include toxic RNA gain-of-function, mitochondrial dysfunction, channelopathies, autophagy and transcription dysregulation. Recent studies have also demonstrated the importance of DNA repair pathways in modifying SCA with CAG expansions. In addition, we summarise the latest technological advances in detecting known and novel repeat expansion in SCA. Finally, we discuss the roles of antisense oligonucleotides and RNA-based therapy as potential treatments. Electronic supplementary material The online version of this article (10.1007/s00415-018-9076-4) contains supplementary material, which is available to authorized users.

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“…Significant dysfunctions in the autophagy pathway have been identified in several neurodegenerative diseases [158,159]. Importantly, studies on both patients [160][161][162] and preclinical experimental models [160,161,[163][164][165] indicated that alterations of the autophagic flux are implicated in different types of cerebellar ataxia. In particular, some forms of spinocerebellar ataxias (SCA1-3; 6,7,17) and dentatorubral-pallidoluysian atrophy are caused by the abnormal CAG repeat expansion [166], resulting in extended polyglutamine (polyQ) tracts, aggregates, and intracellular inclusions, which are a substrate of autophagy-mediated degradation.…”

Section: Cellular Mechanisms Underlying Functional Cerebellar Reservementioning

confidence: 99%

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

et al. 2019

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Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

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Fibroblasts of Machado Joseph Disease patients reveal autophagy impairment

Cited by 72 publications

References 45 publications

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

Spinocerebellar ataxia: an update

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

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