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Vulnerability of mesostriatal dopaminergic neurons in Parkinson's disease
Tomás González-Hernández1, Ignacio Cruz-Muros, Domingo Afonso-Oramas
1Department of Anatomy, Faculty of Medicine, University of La Laguna Tenerife, Spain.
Abstract:
The term vulnerability was first associated with the midbrain dopaminergic neurons 85 years ago, before they were identified as monoaminergic neurons, when Foix and Nicolesco (1925) reported the loss of neuromelanin containing neurons in the midbrain of patients with post-encephalitic Parkinson's disease (PD). A few years later, Hassler (1938) showed that degeneration is more intense in the ventral tier of the substantia nigra compacta than in its dorsal tier and the ventral tegmental area (VTA), outlining the concept of differential vulnerability of midbrain dopaminergic (DA-) neurons. Nowadays, we know that other neuronal groups degenerate in PD, but the massive loss of nigral DA-cells is its pathological hallmark, having a pivotal position in the pathophysiology of the disease as it is responsible for the motor symptoms. Data from humans as well as cellular and animal models indicate that DA-cell degeneration is a complex process, probably precipitated by the convergence of different risk factors, mediated by oxidative stress, and involving pathogenic factors arising within the DA-neuron (intrinsic factors), and from its environment and distant interconnected brain regions (extrinsic factors). In light of current data, intrinsic factors seem to be preferentially involved in the first steps of the degenerative process, and extrinsic factors in its progression. A controversial issue is the relative weight of the impairment of common cell functions, such as energy metabolism and proteostasis, and specific dopaminergic functions, such as pacemaking activity and DA handling, in the pathogenesis of DA-cell degeneration. Here we will review the current knowledge about the relevance of these factors at the beginning and during the progression of PD, and in the differential vulnerability of midbrain DA-cells.
Insights
Parkinson's disease (PD) involves the degeneration of midbrain dopaminergic (DA) neurons, a process influenced by both internal and external factors. Understanding these factors is key to addressing the differential vulnerability observed in DA-cell loss during PD progression.
Area of Science:
- Neuroscience
- Pathology
- Neurodegenerative Diseases
Background:
- The concept of "vulnerability" in midbrain dopaminergic (DA) neurons dates back to observations of neuronal loss in post-encephalitic Parkinson's disease (PD).
- Differential degeneration patterns, particularly in the substantia nigra compacta, highlight the selective vulnerability of these DA neurons.
- Massive loss of nigral DA neurons is a pathological hallmark of PD, directly linked to motor symptoms.
Purpose of the Study:
- To review current knowledge on factors contributing to DA-cell degeneration in PD.
- To explore the roles of intrinsic and extrinsic factors in the initiation and progression of DA-cell loss.
- To discuss the differential vulnerability of midbrain DA neurons in the context of PD pathogenesis.
Main Methods:
- Review of existing human data, cellular models, and animal models of PD.
- Analysis of pathogenic factors, including oxidative stress, intrinsic neuronal factors, and extrinsic environmental/brain region factors.
- Examination of the contribution of impaired cell functions (energy metabolism, proteostasis) versus specific DA functions (pacemaking, DA handling).
Main Results:
- DA-cell degeneration in PD is a complex process influenced by multiple risk factors and oxidative stress.
- Intrinsic factors appear crucial in the early stages of degeneration, while extrinsic factors contribute to its progression.
- The relative importance of common cellular functions versus specific dopaminergic functions in DA-cell degeneration remains a subject of debate.
Conclusions:
- Midbrain DA-cell degeneration in PD is multifactorial, involving a complex interplay of intrinsic and extrinsic factors.
- Understanding the differential vulnerability of DA neurons is critical for elucidating PD pathophysiology.
- Further research is needed to clarify the precise roles of various cellular and functional impairments in PD pathogenesis.
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