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Review
. 2016 Oct;139 Suppl 1(Suppl 1):91-107.
doi: 10.1111/jnc.13266. Epub 2015 Sep 3.

Genes associated with Parkinson's disease: regulation of autophagy and beyond

Alexandra Beilina  1 , Mark R Cookson  2
Affiliations
Review

Genes associated with Parkinson's disease: regulation of autophagy and beyond

Alexandra Beilina et al. J Neurochem. 2016 Oct.

Abstract

Substantial progress has been made in the genetic basis of Parkinson's disease (PD). In particular, by identifying genes that segregate with inherited PD or show robust association with sporadic disease, and by showing the same genes are found on both lists, we have generated an outline of the cause of this condition. Here, we will discuss what those genes tell us about the underlying biology of PD. We specifically discuss the relationships between protein products of PD genes and show that common links include regulation of the autophagy-lysosome system, an important way by which cells recycle proteins and organelles. We also discuss whether all PD genes should be considered to be in the same pathway and propose that in some cases the relationships are closer, whereas in other cases the interactions are more distant and might be considered separate. Beilina and Cookson review the links between genes for Parkinson's disease (red) and the autophagy-lysosomal system. They propose the hypothesis that many of the known PD genes can be assigned to pathways that affect (I) turnover of mitochondria via mitophagy (II) turnover of several vesicular structures via macroautophagy or chaperone-mediated autophagy or (III) general lysosome function. This article is part of a special issue on Parkinson disease.

Keywords: Parkinson's disease; chaperone-mediated autophagy; genetics; lysosomes; mitophagy; protein complexes.

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Conflict of interest statement

Conflict of interest disclosure

The authors have no conflict of interest to declare.

Figures

Fig. 1
Fig. 1
Mitophagy. Mitochondria normally exhibit polarization across their membranes as a result of an imbalance in H+ ion flow because of oxidative metabolism – this is known as mitochondrial membrane potential (ΔΨm). Mitochondria can be depolarized, in which case they can undergo fission and either recover membrane potential and rejoin the network by fusion or become isolated and be turned over via mitophagy. The mechanisms of mitophagy involve several PD-related genes. PINK1 (pink in the diagram) becomes stabilized on the mitochondrial surface, then phosphorylating ubiquitin (small black dots). Parkin is then recruited from the cytosol and activated, adding phosphorylated ubiquitin to multiple proteins on the outer mitochondrial membrane. Some data suggest that the adaptor protein Fbxo7 is required for this step. Once marked in this way, the damaged mitochondria are then engulfed by the nascent phagophore, a de novo lipid structure marked by the accumulation of LC3 (black ovals), a ubiquitin-like molecule that is lapidated once autophagy is initiated. The autophagic vesicle is completed and fuses with lysosomes, resulting in degradation of the damaged mitochondria.
Fig. 2
Fig. 2
Chaperone-mediated autophagy (CMA) and macroautophagy. At least two PD genes are thought to play roles in CMA and macroautophagy, shown here integrated into some of the other major vesicular transport systems in cells. α-Synuclein (red) is associated with several lipid structures, but particularly in vesicles coming from the plasma membrane. When bound to a complex of chaperones (mainly Hsc70) and co-chaperones, α-synuclein can be transported to the lysosome and translocated through a pore formed by dimerized LAMP2A and degraded. Recycling vesicles can fuse with endosomes that then mature, a process that includes switches of small GTPases from Rab5 to Rab7. Late endosomes fuse with autophagic vesicles to generate amphisomes, which then also target their contents to the lysosome. The endosomal system is also important in the sorting of proteins to the lysosome; here in blue the protease cathepsin D is shown maturing through the ER and Golgi via binding to mannose-6-phosphate that is recognized by the cation-independent mannose-6-phosphate receptor (CI-M6PR). A portion of CI-M6PR is recycled back to the trans-Golgi network (TGN) via the retromer complex (light blue). Two genes for PD, LRRK2 (shown as a dimeric protein in brown) and VPS35 are involved in different aspects of these mechanisms. LRRK2 can be found in several different vesicular structures from the TGN where it interacts with the PD risk factor protein Rab7L1, through several autophagic vesicles. Current data support the hypothesis that LRRK2 has a general inhibitory effect on autophagy. VPS35 is a direct component of the retromer and is reported to change interactions within the recycling aspect of this pathway. Although the diagram here presents the CMA and macroautophagy pathways as somewhat distinct, in practice they are likely to influence each other. For example, there is some evidence that mutant forms of α-synuclein and LRRK2 both inhibit CMA.
Fig. 3
Fig. 3
Lysosomal proteins. Similar to figure 2, two additional genes for PD are shown in the context of the regulation of some of the broader aspects of function in the autophagy–lysosomal system. Glucocere-brosidase (GCase) is, like cathepsin D in figure 2, trafficked from the ER through the Golgi to the lysosome where it catalyzes the degradation of glycosylceramide to glucose and ceramides (in the reaction outlined in the box). Mutant forms of GCase are often improperly folded and degraded by the proteasome, leading to accumulation of glucosylceramides. ATP13A2 is reported to be present on a number of regulatory vesicles in the autophagy–lysosome system, where it allows for the transport of Zn and potentially other divalent metal cations (not shown) into the lumen of those vesicles. There is some evidence that amphisomes containing ATP13A2 can fuse with the plasma membrane, thus influencing exocytosis.
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