Machado-Joseph-Azorean Disease

Fowler, Hilton L.

doi:10.1001/archneur.1984.04050200027013

Cited by 37 publications

(9 citation statements)

References 16 publications

(10 reference statements)

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“…It is part of a group of nine known polyglutamine (polyQ) disorders which share expanded CAG repeat mutations that translate into polyQ tracts [5], [6]. The signs and symptoms of MJD include progressive postural instability, gait and limb ataxia, weight loss and, in severe cases, premature death [2], [7], [8]. The pathology of MJD includes severe neuronal loss in the spinal cord and selective brain regions such as dentate nuclei (cerebellum), pontine nuclei (brainstem), substantia nigra, and striatum [2], [7]–[10].…”

Section: Introductionmentioning

confidence: 99%

Silencing Mutant Ataxin-3 Rescues Motor Deficits and Neuropathology in Machado-Joseph Disease Transgenic Mice

et al. 2013

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Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein – ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the disease, supporting the use of this strategy for therapy of MJD.

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Section: Introductionmentioning

confidence: 99%

Silencing Mutant Ataxin-3 Rescues Motor Deficits and Neuropathology in Machado-Joseph Disease Transgenic Mice

et al. 2013

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“…The signs and symptoms include progressive postural instability, gait and limb ataxia, weight loss, and, in severe cases, premature death (Fowler, 1984;Sudarsky and Coutinho, 1995). The pathology of MJD includes severe neuronal loss in the spinal cord and selective brain regions such as dentate nuclei (cerebellum), pontine nuclei (brainstem), substantia nigra (basal ganglia), and, to a lesser degree, cerebellar cortex (Fowler, 1984;Sudarsky and Coutinho, 1995;Durr et al, 1996). Brain regions such as the cerebral cortex are typically spared from severe neuronal demise (Fowler, 1984;Sudarsky and Coutinho, 1995;Durr et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…The pathology of MJD includes severe neuronal loss in the spinal cord and selective brain regions such as dentate nuclei (cerebellum), pontine nuclei (brainstem), substantia nigra (basal ganglia), and, to a lesser degree, cerebellar cortex (Fowler, 1984;Sudarsky and Coutinho, 1995;Durr et al, 1996). Brain regions such as the cerebral cortex are typically spared from severe neuronal demise (Fowler, 1984;Sudarsky and Coutinho, 1995;Durr et al, 1996). Intranuclear inclusions are detected in affected and spared neurons of MJD patients (Paulson et al, 1997b;Schmidt et al, 1998;Yamada et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Goti¹,

Katzen²,

Mez³

et al. 2004

J. Neurosci.

181

244

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Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by ataxin-3 with a polyglutamine expansion. It isproposed that a toxic cleavage fragment of mutant ataxin-3 alternatively spliced isoform mjd1a triggers neurodegeneration, although this fragment has not yet been detected in the brains of MJD patients or in animal models. We have now generated transgenic mice expressing human mutant (Q71) or normal (Q20) ataxin-3 mjd1a under the control of the mouse prion promoter. Q71 transgenic mice expressing mutant ataxin-3 mjd1a above a critical level developed a phenotype similar to MJD including progressive postural instability, gait and limb ataxia, weight loss, premature death, neuronal intranuclear inclusions, and decreased tyrosine hydroxylase-positive neurons in the substantia nigra (determined by unbiased stereology). Q20 transgenic mice had normal behavior and pathology. Brains from sick Q71 transgenic mice contained an abundant mutant ataxin-3 mjd1a putative-cleavage fragment (Fragment), which was scarce in normal Q71 transgenic mice. Reactivity of the Fragment with a panel of antibodies and comigration with truncations of mutant ataxin-3 revealed that it contained residues C terminal to amino acid 221 to include the polyglutamine expansion. A similar portion of mutant ataxin-3 mjd1a expressed in transfected neuroblastoma cells was toxic above a critical concentration. The Fragment was more abundant in two affected brain regions of MJD patients. Thus, we have developed a murine model for mutant ataxin-3 mjd1a toxicity and identified a putativecleavage fragment of the disease protein in the brains of these transgenic mice and MJD patients that is cytotoxic above a critical concentration.

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“…In clinical descriptions of SCA2, the frequency of cognitive deficits varies from 5 to 19 % [7,9,15,41]. Most clinical investigations of SCA3 individuals of various ethnic origins emphasise the absence of cognitive dysfunction [8,11,17,34]. In a large clinical description of Portuguese SCA3 patients, Sequeiros and Coutinho found mild loss of memory to be restricted to 2 out of 143 individuals [39].…”

Section: Introductionmentioning

confidence: 99%

Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3

Bürk¹,

Globas²,

Bösch³

et al. 2003

Journal of Neurology

201

157

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Cognitive impairment was studied in distinct types of spinocerebellar ataxia (SCA): eleven SCA1, 14 SCA2, and 11 SCA3 individuals and 8 age- and IQ- matched controls. All were submitted to a neuropsychological test battery that comprised tests for IQ, attention, executive function, verbal and visuospatial memory. Executive dysfunction was prominent in SCA1 as compared with controls and all other SCA types. Mild deficits of verbal memory were present in SCA1, SCA2 and SCA3. The neuropathological pattern in different SCA types suggests that these cognitive deficits are not likely to be contingent upon cerebellar degeneration but to result from disruption of a cerebrocerebellar circuitry presumably at the pontine level.

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Machado-Joseph-Azorean Disease

Cited by 37 publications

References 16 publications

Silencing Mutant Ataxin-3 Rescues Motor Deficits and Neuropathology in Machado-Joseph Disease Transgenic Mice

Silencing Mutant Ataxin-3 Rescues Motor Deficits and Neuropathology in Machado-Joseph Disease Transgenic Mice

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3

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