Parkinson's disease: leucine-rich repeat kinase 2 and autophagy, intimate enemies

Abstract

Parkinson's disease is the second common neurodegenerative disorder, after Alzheimer's disease. It is a clinical syndrome characterized by loss of dopamine-generating cells in the substancia nigra, a region of the midbrain. The etiology of Parkinson's disease has long been through to involve both genetic and environmental factors. Mutations in the leucine-rich repeat kinase 2 gene cause late-onset Parkinson's disease with a clinical appearance indistinguishable from Parkinson's disease idiopathic. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damage proteins and cytoplasmic organelles. This degradative process has been associated with cellular dysfunction in neurodegenerative processes including Parkinson's disease. We discuss the role of leucine-rich repeat kinase 2 in autophagy, and how the deregulations of this degradative mechanism in cells can be implicated in the Parkinson's disease etiology.

Figure 1

LRRK2 domain structure with homodimeric conformation. LRRK2 is a protein that contains ankyrin repeats, leucine-rich repeats, a catalytic core of the protein contains a GTP-binding ROC (Ras of complex proteins), COR domain (C-terminal of ROC), kinase domain. At the C-terminus is a WD40 repeat followed by a short C-terminal tail.

Figure 2

Schematic Illustration on 3D of the autophagy flux. The first step consists of the formation of isolation membranes (phagophore) and elongation of this membrane for sequester the material to degraded (autophagosome). Finally a lysosome is fused with the autophagosome (autophagolysosome) and the cargo is degraded.

Figure 3

Molecular regulation of autophagy. In the figure, the factors that stimulate autophagy (green) are JNK, ERK1/2, ROS, or PI3K class III, whereas the inhibitory factors (red) are NF-κB, mTOR, caspase 8, Bcl-2, or p38.

Figure 4

Diagram with the possible sites of interaction LRRK2-autophagy. The figure shows the different routes involved in the regulation of autophagy that may be LRRK2 dependent.