Parkinson's disease and mitophagy: an emerging role for LRRK2

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress - so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

Keywords: Parkinsons disease; autophagy; leucine-rich repeat kinase; mitophagy.

Figure 1.. Parkinson's disease-linked genes independently implicated in mitophagy.

Homeostasis: PINK1 is imported within the mitochondria where it is cleaved and is then exported for degradation. Cardiolipin is present at the internal mitochondrial membrane where it interacts with the Complex I–Complex III–Complex IV supercomplex. Mitochondrial stress: Oxidized DJ-1 is translocated to the nucleus where it acts as a transcription factor for genes involved in ROS detoxication. Uncontrolled stress: Following loss of mitochondrial membrane potential, PINK1 is stabilized at the surface of the outer mitochondrial membrane where it phosphorylates Parkin. Cardiolipin is translocated to the cytosolic side of the outer mitochondrial membrane. Signal amplification: Activated Parkin and FBXO7 ubiquitylate proteins on the outer mitochondrial membrane. Cardiolipin interacts with α-synuclein to recruit LC3. Phagophore Formation: The amplificated signal recruits the autophagosome machinery that initiates the formation of the phagophore. Trafficking to the lysosome: The newly formed phagosome is trafficked to the lysosome with the help of the retromer complex (VPS35, VPS26, and VPS29). VPS35 enhances the kinase activity of LRRK2. Fusion with the lysosome: LRRK2 phosphorylates Rab10, which in turn promote the translocation of JIP4 to the lysosome to form sensing tubules, enabling the sorting of vesicles. Mitochondrial degradation: The defective mitochondria is degraded in the mitolysosome that contains GBA1.

Figure 2.. Roles of LRRK2 in mitophagy.

Schematic of LRRK2 domain structure is shown at the top and pathogenic mutations in the catalytic domains are noted. VPS35, a retromer subunit, enhances LRRK2 kinase activity. Parkin-dependent mitophagy: Increased LRRK2 activity negatively impacts PINK1/Parkin-dependent mitophagy by reducing PARKIN interaction with the TOMM complex and DRP1, as well as reducing Rab10 recruitment to mitochondria and the interaction between optineurin (OPTN) with ubiquitylated OMM proteins. Basal mitophagy: LRRK2 kinase activity also impairs basal mitophagy and lysosomal function (which impacts the end point of mitophagy). Lysosomal function: At the lysosome LRRK2 regulates sorting via Rab10 phosphorylation and JIP4 and it negatively regulates the function of GBA1. It also impacts the vacuolar ATPase, leading to a higher lysosomal pH, which in turn impacts cathepsin-mediated degradation of α-synuclein. LRRK2 kinase inhibitors attenuate many of these effects, for example, inhibitors such as GSK3357679A, rescues the mitophagy defects in mice carrying the pathogenic G2019S LRRK2 mutation.