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Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome
Ebrahim Abdul Shukkur1, Atsushi Shimohata, Takumi Akagi
1Laboratory for Neurogenetics, RIKEN Brain Science Institute, Saitama, Japan.
Human Molecular Genetics
|August 8, 2006
Summary
Genes on chromosome 21, excluding APP and SOD1, cause oxidative stress and mitochondrial dysfunction in Down syndrome (DS) mouse models. This contributes to neurodegeneration and mental retardation in DS.
Area of Science:
- Genetics
- Neuroscience
- Biochemistry
Background:
- Down syndrome (DS), or trisomy 21, is the most common genetic cause of intellectual disability.
- Gene dosage imbalance on chromosome 21, particularly overexpression of SOD1 and APP, is implicated in DS-related oxidative stress and neurodegeneration.
Purpose of the Study:
- To investigate the role of genes on a segmental trisomy 16 mouse model (Ts1Cje) that excludes APP and SOD1 in DS pathogenesis.
- To determine if genes other than APP and SOD1 on trisomic regions contribute to DS-associated neurodevelopmental deficits.
Main Methods:
- Analysis of Ts1Cje mouse brains for mitochondrial function, reactive oxygen species (ROS) levels, tau phosphorylation, and enzyme activities.
- Assessment of amyloid-beta precursor protein (AbetaPP) metabolism in Ts1Cje models.
Main Results:
- Ts1Cje mouse brains exhibited reduced mitochondrial membrane potential and ATP production.
- Increased ROS, tau hyperphosphorylation, and elevated GSK3beta and JNK/SAPK activities were observed.
- AbetaPP metabolism remained unaltered in the Ts1Cje model.
Conclusions:
- Genes within the trisomic segment of Ts1Cje, distinct from APP and SOD1, induce oxidative stress and mitochondrial dysfunction.
- These cellular changes, including tau hyperphosphorylation, are critical factors in the neurodevelopmental pathology of Down syndrome.