Genetics and genomics of Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. Although best described as a movement disorder, the condition has prominent autonomic, cognitive, psychiatric, sensory and sleep components. Striatal dopaminergic innervation and nigral neurons are progressively lost, with associated Lewy pathology readily apparent on autopsy. Nevertheless, knowledge of the molecular events leading to this pathophysiology is limited. Current therapies offer symptomatic benefit but they fail to slow progression and patients continue to deteriorate. Recent discoveries in sporadic, Mendelian and more complex forms of parkinsonism provide novel insight into disease etiology; 28 genes, including those encoding alpha-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2) and microtubule-associated protein tau (MAPT), have been linked and/or associated with PD. A consensus regarding the affected biological pathways and molecular processes has also started to emerge. In early-onset and more a typical PD, deficits in mitophagy pathways and lysosomal function appear to be prominent. By contrast, in more typical late-onset PD, chronic, albeit subtle, dysfunction in synaptic transmission, early endosomal trafficking and receptor recycling, as well as chaperone-mediated autophagy, provide a unifying synthesis of the molecular pathways involved. Disease-modification (neuroprotection) is no longer such an elusive goal given the unparalleled opportunity for diagnosis, translational neuroscience and therapeutic development provided by genetic discovery.

Figure 1

Cellular processes implicated in familial late-onset, Lewy body parkinsonism. In late onset parkinsonism, which is most reminiscent of Lewy body PD, a novel synthesis is emerging whereby regulatory steps in synaptic neurotransmission, receptor recycling, endosomal trafficking and lysosomal degradation are controlled by relatively few proteins. Studies in neurons and brain are limited but many reciprocal connections are apparent [8]. For example, (a) SNCA functions with heat shock chaperone Hsc70 and SNAP25 to promote membrane SNARE complex assembly and exocytosis in neurotransmission. (b) In mammalian cells, LRRK2 may also regulate cleavage of invaginated endocytic membrane through interaction with dynamin. Several other genes, including DNAJC6 (with homology to GAK) and SYNJ1, encode proteins important in clathrin uncoating. In Drosophila, LRK1 (the homolog of mammalian LRRK1 and LRRK2) phosphorylates endophilin A to directly regulate endocytosis. In the mammalian striatum the expression levels of SNCA and endophilin A are reciprocally related. (c) In the endosome, VPS35 and the retromer cargo-selective-complex (CSC; comprising VPS35-VPS26 and VPS29) play an important role in membrane protein cargo sorting. The CSC is best described in endosome to trans-Golgi network retrieval in the soma, most specifically in recycling cation-independent mannose-6-phosphate receptor that traffics acidic hydrolases (including GBA) to the lysosome. However, recent studies in neurons have revealed that VPS35 and WASH are also crucial in protein recycling (d) of specific synaptic receptors from early endosome to plasma membrane, and (e) in the V-ATPase required for lysosomal acidification. Importantly, CSC trafficking can be mediated by sorting nexin interaction with dynactin p150^Glued (DCTN1), dynein, tau (MAPT) and microtubules, or via the WASH complex, DNAJC13 and actin polymerization. DNAJC13 was first described in endocytosis in C. elegans, rather than in post-endocytic trafficking, and like SNCA requires Hsc70 to function. LRRK2 has also been shown to interact with VPS35 and microtubules, and like SNCA may be intrinsically targeted to lysosomal membranes by protein motifs for chaperone-mediated autophagy. Clearance of insoluble SNCA aggregates is also mediated by the endosomal system and lysosomal degradation [153]. Several other lysosomal proteins, including ATP13A2 and ATP6AP2, have been implicated in atypical parkinsonism. EIF4G1, through mTOR regulation of protein translation, serves to balance autophagic activity and metabolism or ATP levels, whereas (f) PINK1 and Parkin are intrinsically involved in mitochondrial quality control in early onset parknsonism.