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Environmental Modulations of the Number of Midbrain Dopamine Neurons in Adult Mice
Published on: January 20, 2015
Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response
Roberta Filograna1, Seungmin Lee1, Katarína Tiklová2
1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Abstract:
Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.
Insights
Mitochondrial dysfunction in adult dopamine neurons causes Parkinson's-like symptoms in mice. An early immune response precedes neurodegeneration, suggesting glial cell involvement in Parkinson's disease pathogenesis.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Neurodegenerative Diseases
Background:
- Mitochondrial defects are implicated in Parkinson's disease (PD).
- The causal role of adult-onset mitochondrial dysfunction in PD pathogenesis is unclear.
- Mitofusin 2 (MFN2) is crucial for mitochondrial network homeostasis.
Purpose of the Study:
- To investigate the impact of adult-onset mitochondrial dysfunction in midbrain dopamine (DA) neurons on PD.
- To elucidate the early pathophysiological events following mitochondrial damage in DA neurons.
Main Methods:
- Developed a mouse model with targeted deletion of Mitofusin 2 (MFN2) in adult midbrain DA neurons.
- Analyzed DA neuron mitochondrial function, neurodegeneration, and parkinsonism.
- Performed transcriptomic analysis of isolated DA neurons.
Main Results:
- MFN2 knockout mice exhibited progressive DA neuron-specific mitochondrial dysfunction, neurodegeneration, and parkinsonism.
- Mitochondrial dysfunction triggered an early immune response preceding morphological and functional deficits.
- Transcriptomic data revealed an immune response that occurred before mitochondrial swelling, mtDNA depletion, and cell death.
Conclusions:
- Adult-onset mitochondrial dysfunction in midbrain DA neurons can induce PD-like pathology.
- An early immune response is a key pathological event in this model.
- Neuronal death may be promoted non-cell autonomously through glial cell activation and cross-talk.
