Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function
Adam W Oaks1, Maya Frankfurt, David I Finkelstein
1Laboratory of Molecular Neurochemistry, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
Plos One
|April 6, 2013
Summary
Mice with A53T alpha-synuclein developed Parkinson's-like motor deficits and behavioral changes. These alterations involved dopamine transporter function and Tau phosphorylation, highlighting synuclein's role in neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- The A53T mutant alpha-synuclein mouse model is crucial for studying Parkinson's disease (PD).
- Alpha-synuclein accumulation in this model leads to motor impairment and early death.
- Pre-symptomatic behavioral changes suggest roles beyond pathology, possibly in neurotransmission.
Purpose of the Study:
- To investigate motor activity, anxiety-like, and depressive-like behaviors throughout the lifespan of A53T mice.
- To explore the relationship between alpha-synuclein, dopamine transporter (DAT) function, and Tau phosphorylation in PD pathogenesis.
- To understand the involvement of the synuclein family and Tau phosphorylation in nigrostriatal pathway dysfunction.
Main Methods:
- Longitudinal analysis of motor activity, anxiety-like, and depressive-like behaviors in A53T mice.
- Measurement of dopamine transporter (DAT) distribution and striatal re-uptake function.
- Assessment of beta-synuclein, gamma synuclein expression, and Tau kinase activation/phosphorylation.
- Histological analysis of neuron counts in the substantia nigra and dendritic spine density in the striatum.
Main Results:
- Young A53T mice exhibited increased DAT membrane distribution and striatal re-uptake.
- DAT function declined with aging, accompanied by increased beta- and gamma-synuclein expression.
- Transient Tau kinase activation and hyperphosphorylation were observed before dopamine uptake normalization.
- Aged mice showed reduced substantia nigra neuron counts but maintained striatal medium spiny neuron dendritic spine density.
Conclusions:
- Behavioral and motor deficits in A53T mice manifest both pre- and post-disease onset.
- Synuclein family proteins and Tau phosphorylation are implicated in the response to dopaminergic dysfunction.
- The findings provide insights into the complex interplay of proteins in Parkinson's disease progression.
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