Machado–Joseph disease/spinocerebellar ataxia type 3

Paulson, Henry L.

doi:10.1016/b978-0-444-51892-7.00027-9

Cited by 160 publications

(146 citation statements)

References 131 publications

Supporting

Mentioning

141

Contrasting

Unclassified

Order By: Relevance

“…The age of onset varies considerably, although on average repeat length is inversely correlated with age of onset. Patients typically present first with progressive gait imbalance and speech difficulties, eventually developing occulomotor difficulties, spasticity, dystonia and, eventually, severe dysarthria and dysphagia [33]. …”

Section: Altered Intrinsic Purkinje Neuron Pacemaking As a Primary Drmentioning

confidence: 99%

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Chopra

Shakkottai

2014

Future Neurol.

View full text Add to dashboard Cite

The cerebellum is an important structure for accurate control and timing of movement, and Purkinje neurons in the cerebellar cortex are key players in cerebellar motor control. Cerebellar dysfunction can result in ataxia, a disorder characterized by postural instability, gait disturbances and motor incoordination. Cerebellar ataxia is a symptom of a number of conditions, and the emerging evidence that Purkinje neuron dysfunction, in particular, abnormal Purkinje neuron repetitive firing, is a major driver of motor dysfunction in a subset of dominantly inherited ataxias is dicussed. Abnormalities in Purkinje neuron excitability that are observed in mouse models of each of these disorders, and where appropriate describe studies linking particular ion channels to aberrant excitability are also discussed. Common mechanisms of dysfunction and speculate about potential therapeutic targets, suggesting that Purkinje neuron firing abnormalities are a novel target for improving motor dysfunction in patients with some forms of dominantly inherited ataxia are proposed.

show abstract

Section: Altered Intrinsic Purkinje Neuron Pacemaking As a Primary Drmentioning

confidence: 99%

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Chopra

Shakkottai

2014

Future Neurol.

View full text Add to dashboard Cite

show abstract

“…The mechanisms by which mutant ataxin-3 induces neurodegeneration have been extensively studied but remain incompletely understood [reviewed in ref. [13]]. Difficulties in fully understanding the pathogenic process leading to the neurotoxicity of mutant ataxin-3 are reflected in the current lack of specific strategies to reverse morbidity.…”

Section: Introductionmentioning

confidence: 99%

Patterns of Mitochondrial DNA Damage in Blood and Brain Tissues of a Transgenic Mouse Model of Machado-Joseph Disease

et al. 2012

View full text Add to dashboard Cite

Background: Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia caused by a CAG tract expansions in the ATXN3 gene. Patterns of mitochondrial damage associated with pathological findings of brain tissues could provide molecular biomarkers of this disorder. Objective: The potential of mitochondrial DNA (mtDNA) damage as a biomarker of MJD progression was investigated using a transgenic mouse model. Methods: DNA was obtained from affected (pontine nuclei) and nonaffected tissues (hippocampus and blood) of transgenic animals of three distinct age groups: 8 weeks, before onset of the phenotype; 16 weeks, at onset, and 24 weeks, at well-established phenotype. Wild-type littermate mice, serving as controls, were analyzed for the same tissues and age groups. mtDNA damage was studied by fluorescence-based quantitative PCR in 84 transgenic and 93 wild-type samples. Results: A clear pattern of decrease in mtDNA copy number with age and accumulation of 3,867-bp deletions at the initial stages (both being more pronounced in transgenic mice) was observed. Pontine nuclei, the affected tissue in transgenic mice, displayed 1.5 times less copies of mtDNA than nonaffected brain tissue hippocampus (odds ratio = 1.21). Pontine nuclei displayed the highest percentage of mtDNA deletions (6.05% more in transgenic mice). Conclusion: These results suggest that mtDNA damage is related to the initiation of the phenotype in transgenic mice; mtDNA 3,867-bp deletions may be a biomarker of the initial stages of the disease.

show abstract

“…Indeed, the involvement of the cerebellum, the anterior horn of the spinal cord, and the peripheral nerves are often observed in SCA3 patients (Paulson, 2012). It is also known that the age of symptom onset in the juvenile form of SCA3 patients with a long 86 CAG repeat can be as early as 5 years (Zhou et al 1997; Paulson, 2012), and that in SCA3, patients with homozygous expansions can be as young as 4 years old (Carvalho et al 2008), resembling the relatively young onset of our transgenic marmoset line expressing hyperexpanded CAG repeats.…”

Section: Discussionmentioning

confidence: 99%

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

Tomioka

Ishibashi

Minakawa

et al. 2017

eNeuro

View full text Add to dashboard Cite

Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.

show abstract

Machado–Joseph disease/spinocerebellar ataxia type 3

Cited by 160 publications

References 131 publications

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Patterns of Mitochondrial DNA Damage in Blood and Brain Tissues of a Transgenic Mouse Model of Machado-Joseph Disease

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

Contact Info

Product

Resources

About