Abstract
Numerous disorders of the central nervous system (CNS) are attributed to the selective death of distinct neuronal cell populations. Interestingly, in many of these conditions, a specific subset of neurons is extremely prone to degeneration while other, very similar neurons are less affected or even spared for many years. In Parkinson’s disease (PD), the motor manifestations are primarily linked to the selective, progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). In contrast, the very similar DA neurons in the ventral tegmental area (VTA) demonstrate a much lower degree of degeneration. Elucidating the molecular mechanisms underlying the phenomenon of differential DA vulnerability in PD has proven extremely challenging. Moreover, an increasing number of studies demonstrate that considerable molecular and electrophysiologic heterogeneity exists among the DA neurons within the SNpc as well as those within the VTA, adding yet another layer of complexity to the selective DA vulnerability observed in PD. The discovery of key pathways that regulate this differential susceptibility of DA neurons to degeneration holds great potential for the discovery of novel drug targets and the development of promising neuroprotective treatment strategies. This review provides an update on the molecular basis of the differential vulnerability of midbrain DA neurons in PD and highlights the most recent developments in this field.
Highlights
The selective death of distinct neuronal cell populations is the key feature of many disorders of the central nervous system (CNS)
Fu et al did not confirm that more substantia nigra pars compacta (SNpc) DA neurons express high levels of GIRK2 than ventral tegmental area (VTA) DA neurons (Fu et al, 2012). These results indicate that GIRK2 is unlikely to be a marker to distinguish between dorsal and ventral tier SNpc DA neurons, and that the GIRK2 expression pattern does not correlate with the differential vulnerability of these two SNpc DA neuron subgroups in Parkinson’s disease (PD)
Studies focusing on the identification and characterization of differentially expressed proteins have revealed that the candidate proteins identified to date are not exclusively expressed in either SNpc or VTA DA neurons but rather enriched in either neuronal group at best
Summary
The selective death of distinct neuronal cell populations is the key feature of many disorders of the central nervous system (CNS). Examples of diseases that are characterized by the selective degeneration of neurons in the CNS include Alzheimer’s disease, Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and autosomal recessive proximal Spinal Muscular Atrophy. It is largely unknown why different groups of neurons are highly vulnerable to degeneration in different diseases. Autosomal recessive proximal spinal muscular atrophy is characterized by the progressive selective loss in particular of the lower motor neurons in the anterior horns of the spinal cord, while upper motor neurons are spared (Talbot and Davies, 2001).
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