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Primary Culture of Mouse Dopaminergic Neurons
Published on: September 8, 2014
What causes the death of dopaminergic neurons in Parkinson's disease?
D James Surmeier1, Jaime N Guzman, Javier Sanchez-Padilla
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. j-surmeier@northwestern.edu
Abstract:
The factors governing neuronal loss in Parkinson's disease (PD) are the subject of continuing speculation and experimental study. In recent years, factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease aetiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This chapter focuses on recent studies showing that the neurons at greatest risk in PD--substantia nigra pars compacta (SNc) dopamine (DA) neurons--have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of SNc DA neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cell-specific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.
Insights
Parkinson's disease (PD) neuronal loss may stem from cell-specific factors, particularly dopamine (DA) neuron vulnerability due to L-type calcium channel activity. Targeting these channels offers a novel neuroprotective strategy for PD.
Area of Science:
- Neuroscience
- Cell Biology
- Neurodegenerative Diseases
Background:
- Parkinson's disease (PD) pathogenesis is debated, with focus on pan-cellular factors like genetics and toxins.
- The specific vulnerability of substantia nigra pars compacta (SNc) dopamine (DA) neurons in PD remains incompletely explained.
- Cell-specific factors are crucial for understanding the selective neuronal loss observed in PD.
Purpose of the Study:
- To investigate the cell-specific physiological phenotype of SNc DA neurons contributing to PD vulnerability.
- To explore the role of L-type calcium channels in SNc DA neuron susceptibility.
- To identify novel neuroprotective strategies for Parkinson's disease.
Main Methods:
- Analysis of the physiological characteristics of SNc DA neurons.
- Examination of calcium channel activity and its downstream effects.
- Review of existing literature on PD aetiology and potential therapeutic targets.
Main Results:
- SNc DA neurons exhibit a unique phenotype involving sustained calcium entry through L-type calcium channels during pacemaking.
- This calcium influx leads to increased mitochondrial oxidant stress and heightened susceptibility to toxins.
- Cell-specific stress exacerbates the impact of broader cellular challenges (mitochondrial or proteostatic).
Conclusions:
- L-type calcium channel activity in SNc DA neurons is a key factor in their vulnerability in Parkinson's disease.
- Targeting these channels with antagonists presents a promising neuroprotective approach.
- This strategy could complement existing efforts to enhance mitochondrial function in early PD stages.
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