Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

Silva‐Fernandes, Anabela; Duarte‐Silva, Sara; Neves-Carvalho, Andreia; Amorim, Marina F.; Soares‐Cunha, Carina; Oliveira, Pedro F.; Thirstrup, Kenneth; Teixeira-Castro, Andreia; Maciel, Patrı́cia

doi:10.1007/s13311-013-0255-9

Cited by 89 publications

(191 citation statements)

References 51 publications

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“…However, the mechanism underlying the formation of these inclusions is still poorly understood because of the lack of an appropriate model [10, 20]. Recent studies reported a novel mouse model of SCA3 that could be used to study the pathogenesis and treatment of SCA3.…”

Section: Discussionmentioning

confidence: 99%

“…These results were consistent with our in vitro neuronal differentiation of SCA3-iPS cells. Growing evidence has revealed that regulation of autophagy is involved in many human diseases, including neurodegeneration [8, 20]. Aggregation of the mutated form of the disease protein ATXN3 into neuronal nuclear inclusions has been studied extensively in SCA3.…”

Section: Discussionmentioning

confidence: 99%

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Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells

Luo

Niu

et al. 2016

BioMed Research International

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Spinocerebellar ataxia-3 (SCA3) is the most common dominant inherited ataxia worldwide and is caused by an unstable CAG trinucleotide expansion mutation within the ATXN3 gene, resulting in an expanded polyglutamine tract within the ATXN3 protein. Many in vitro studies have examined the role of autophagy in neurodegenerative disorders, including SCA3, using transfection models with expression of pathogenic proteins in normal cells. In the current study, we aimed to develop an improved model for studying SCA3 in vitro using patient-derived cells. The patient-derived iPS cells presented a phenotype similar to that of human embryonic stem cells and could be differentiated into neurons. Additionally, these cells expressed abnormal ATXN3 protein without changes in the CAG repeat length during culture for at least 35 passages as iPS cells, up to 3 passages as neural stem cells, and after 4 weeks of neural differentiation. Furthermore, we demonstrated that neural differentiation in these iPS cells was accompanied by autophagy and that rapamycin promoted autophagy through degradation of mutant ATXN3 proteins in neurally differentiated spinocerebellar ataxia-3 human induced pluripotent stem cells (p < 0.05). In conclusion, patient-derived iPS cells are a good model for studying the mechanisms of SCA3 and may provide a tool for drug discovery in vitro.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells

Luo

Niu

et al. 2016

BioMed Research International

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“…Infrared beams were used to automatically register animals’ movements. We next monitored forelimb strength, hindlimb tonus, hindlimb clasping, negative geotaxis, and gait analysis as previously described (Silva‐Fernandes et al ., 2014). For all tests, scoring was carried out manually by an experimenter blind to the genotype and age of the animals.…”

Section: Methodsmentioning

confidence: 99%

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Lopes

Pinto

et al. 2016

Aging Cell

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SummaryDementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well‐established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor‐related tests, we herein provide evidence of an age‐dependent motor impairment in Tau−/− animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor‐related information. Specifically, we show that the sciatic nerve of old (17–22‐months) Tau−/− mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age‐matched wild‐type (Tau+/+) littermates and younger (4–6 months) Tau−/− and Tau+/+ mice. In addition, the sciatic nerves of Tau−/− mice exhibit a progressive hypomyelination (assessed by g‐ratio) specifically affecting large‐diameter, motor‐related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system.

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“…In SCA3 mice, Hsp90 inhibition with 17-DMAG improved motor function, while decreasing mutant ataxin-3 aggregation and levels, possibly via autophagy activation since 17-DMAG treatment increased both beclin-1 and LC3-II levels [209].…”

Section: Pharmacological Modulation Of Molecular Chaperones In Scas Amentioning

confidence: 95%

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

2016

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Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs, and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here we provide a focused review on Hsp90, Hsp70, and their cochaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer's and Parkinson's diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences.

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Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

Cited by 89 publications

References 51 publications

Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells

Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

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