Genetic neuropathology of Parkinson's disease

Abstract

Parkinson's disease (PD) has long been considered to be a sporadic entity, perhaps with an environmental etiology. However, recent genetic discoveries have challenged this view, as there are many families with diseases of Mendelian inheritance that clinically resemble PD. Here, we will review in detail the neuropathological data relating to familial cases of PD. We will discuss the complicated relationships between the genetically defined cases and the two key pathological events seen in PD, namely loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of protein inclusions, Lewy bodies, in the neurons that survive to the end stage of the disease course. These observations will be synthesized into an overall scheme that emphasizes the two key aspects of the neuropathology as distinct events and suggest that each gene tells us something a little different about the neuropathology of PD.

Keywords: LRRK2; Parkinson's disease; neuropathology; parkin; parkinsonism; tau; α-synuclein.

Figure 1

The relationships between cell death and Lewy body formation with respect to inherited Parkinson's disease. In this schematic, we emphasize that there are two aspects to the pathology of PD; cell loss (blue circle) epitomized by, but not limited to, loss of neurons in the substantia nigra pars compacta and Lewy body formation (magenta circle), which are perinuclear neuronal aggregates of α-synuclein and other proteins, represented here by the orange structure. On the left are other genetic disorders discussed in the text that can have parkinsonism (ie nigral cell loss) as part of their phenotype. On the right is a cartoon (adapted from figure 4 of [69]) suggesting the regional distribution of Lewy bodies in PD where darker colors indicate higher concentrations of α-synuclein pathology. This data suggests that PD is part of a spectrum of disorders that includes diffuse Lewy body disease (DLBD), for example. Finally, underneath the figure are the five PARK genes that are well-described genetically. We suggest here that the recessive genes parkin, PINK1 and DJ-1 (green box) are more informative for cell loss and the dominant genes α-synuclein and LRRK2 (orange box) tell us something about both cell loss and Lewy body formation.