On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson's Disease

Abstract

Significant advances have been made uncovering the factors that render neurons vulnerable in Parkinson's disease (PD). However, the critical pathogenic events leading to cell loss remain poorly understood, complicating the development of disease-modifying interventions. Given that the cardinal motor symptoms and pathology of PD involve the loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc), a majority of the work in the PD field has focused on this specific neuronal population. PD however, is not a disease of DA neurons exclusively: pathology, most notably in the form of Lewy bodies and neurites, has been reported in multiple regions of the central and peripheral nervous system, including for example the locus coeruleus, the dorsal raphe nucleus and the dorsal motor nucleus of the vagus. Cell and/or terminal loss of these additional nuclei is likely to contribute to some of the other symptoms of PD and, most notably to the non-motor features. However, exactly which regions show actual, well-documented, cell loss is presently unclear. In this review we will first examine the strength of the evidence describing the regions of cell loss in idiopathic PD, as well as the order in which this loss occurs. Secondly, we will discuss the neurochemical, morphological and physiological characteristics that render SNc DA neurons vulnerable, and will examine the evidence for these characteristics being shared across PD-affected neuronal populations. The insights raised by focusing on the underpinnings of the selective vulnerability of neurons in PD might be helpful to facilitate the development of new disease-modifying strategies and improve animal models of the disease.

Keywords: Parkinson; cell death; dopamine; neurodegeneration; vulnerability.

Figure 1

(A) Schematic representation of brain regions demonstrating cell loss in Parkinson's disease. These are color-coded based on the evidence of cell loss. Red = 60%, orange = 40%, and yellow = 20%. Color gradients indicate uncertainty in the extent of this cell loss. (B) Summary of the converging hypotheses that may explain the origins of the selective vulnerability of neurons in Parkinson's disease. This includes the exceptionally large axonal arbor of PD-affected neurons, their electrophysiological properties, including calcium-dependent pacemaking, and high levels of oxidant stress in the somatodendritic and axonal domain, all thought to be contributing to cellular dysfunction and cell loss. Pathological protein aggregation and reactive dopamine quinones are considered as additional precipitating factors.