CAG-Dependent Motor Phenotype in a Transgenic Mouse Model of Machado-Joseph Disease
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1
University of Minho, ICVS/Health Sciences School, Portugal
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2
University of Michigan, Department of Neurology, United States
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3
Hospital Fernando Fonseca, Neurology Department, Portugal
Machado-Joseph disease is a hereditary neurodegenerative disorder resulting from the presence of 56-84 consecutive glutamines in the coding region of the ATXN3 gene. The main symptoms of MJD patients include ataxia, spasticity, and ocular movement abnormalities. In order to study the pathogenesis of MJD we have generated a transgenic mouse model expressing mutant ataxin-3 under the control of a general expression promoter (pCMV). We have obtained two lineages, A and B, containing different CAG tract lengths: 94 versus 83 CAGs, respectively. We found that hemizygous (+/-) and homozygous (+/+) mice from lineage A, but not from lineage B, displayed motor coordination impairment (at 16-20 weeks of age) and hypoactivity (SHIRPA protocol), although (+/-) mice from lineage A showed the same total protein expression levels in the brain as (+/+) mice from lineage B. Extensive behavior analysis of several transgenic mice of lineage A, with a range of CAG repeat lengths, allowed us to establish a genotype- phenotype correlation for phenotype manifestation in our mouse model.
Histopathological analysis of MJD transgenic mice brains from lineage A (+/-) versus control animals (-/-) at 96 weeks of age, revealed cell loss and/or atrophy in the lateral dentate (LD), vestibular (Ve) and pontine (Pn) nuclei, thalamus (Th) and substantia nigra (SN). MJD transgenic mice brains also showed astrogliosis in the Ve, SN and Th. Ataxin-3 aggregates were found in the cytoplasm (perinuclear region) of several MJD affected brain regions, namely the LD, SN and Pn.
This novel transgenic mouse model exhibits important features of MJD including the presence of pathological features and a CAG repeat length-dependent motor phenotype.
Conference:
11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009.
Presentation Type:
Poster Presentation
Topic:
Neurodegenerative Disorders
Citation:
Silva-Fernandes
A,
Do-Carmo-Costa
M,
Duarte-Silva
S,
Costa
C and
Maciel
P
(2009). CAG-Dependent Motor Phenotype in a Transgenic Mouse Model of Machado-Joseph Disease.
Front. Neurosci.
Conference Abstract:
11th Meeting of the Portuguese Society for Neuroscience.
doi: 10.3389/conf.neuro.01.2009.11.101
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Received:
10 Aug 2009;
Published Online:
10 Aug 2009.
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Correspondence:
Anabela Silva-Fernandes, University of Minho, ICVS/Health Sciences School, Braga, Portugal, anabelasf@ecsaude.uminho.pt