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.
Highlights
Parkinson’s disease (PD) was first described two centuries ago in An essay on the shaking palsy [1]
PD as a clinical diagnosis is characterized by the detection of significant motor deficits due, in large part, to a loss of dopamine (DA)-containing neurons of the substantia nigra pars compacta (SNc)
We found 90 primary research articles reporting PD-specific cell loss in the following regions (Table 1): the SNc, VTA, amygdala, cortex, dorsal motor nucleus of the vagus (DMV), hypothalamus, laterodorsal tegmental nucleus, locus coeruleus (LC), nucleus basalis of Meynert (NBM), Olfactory bulb (OB), oral pontine reticular nucleus, pedunculopontine nucleus (PPN), pre-supplementary motor cortex, raphe nuclei (RN), supraoptic nucleus, sympathetic/parasympathetic ganglia, and thalamus
Summary
Parkinson’s disease (PD) was first described two centuries ago in An essay on the shaking palsy [1]. It may be useful to focus attention on brain and PNS regions that show documented cell death and/or axonal degeneration, irrespective of the presence or absence of LP This could perhaps provide new perspectives on the actual, more proximate, causes of the major symptoms of the disease and their progression. Another issue to consider is that many of the studies included in this review, including those employing stereology, either did not use age-matched controls, or did not state whether counting was conducted blind to diagnosis Another apparent feature of this literature is the diversity of method iterations used, the varying number of brain regions assessed in each study and, importantly, the stage or type of PD studied (and how this was defined). The definition and clinical stage of PD in most studies
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