Parkinson's: A Disease of Aberrant Vesicle Trafficking

Abstract

Parkinson's disease (PD) is a leading cause of neurodegeneration that is defined by the selective loss of dopaminergic neurons and the accumulation of protein aggregates called Lewy bodies (LBs). The unequivocal identification of Mendelian inherited mutations in 13 genes in PD has provided transforming insights into the pathogenesis of this disease. The mechanistic analysis of several PD genes, including α-synuclein (α-syn), leucine-rich repeat kinase 2 (LRRK2), PTEN-induced kinase 1 (PINK1), and Parkin, has defined central roles for protein aggregation, mitochondrial damage, and defects in endolysosomal trafficking in PD neurodegeneration. In this review, we outline recent advances in our understanding of these gene pathways with a focus on the emergent role of Rab (Ras analog in brain) GTPases and vesicular trafficking as a common mechanism that underpins how mutations in PD genes lead to neuronal loss. These advances have led to previously distinct genes such as vacuolar protein–sorting-associated protein 35 (VPS35) and LRRK2 being implicated in common signaling pathways. A greater understanding of these common nodes of vesicular trafficking will be crucial for linking other PD genes and improving patient stratification in clinical trials underway against α-syn and LRRK2 targets. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 36 is October 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Global ubiquitylation analysis of mitochondria in primary neurons identifies physiological Parkin targets following activation of PINK1

“…We also identified 2 proteins, BNIP3L and DCAKD, whose ubiquitylation was increased in both mouse and human iNeurons albeit at different sites (Figure 2). Furthermore, all of the sites were present on proteins localised at the mitochondrial outer membrane (MOM) consistent with previous studies on how activation of PINK1 and Parkin on the MOM is sufficient to induce clearance of damaged mitochondria via mitophagy (Harper et al, 2018, Singh and Muqit, 2020, Moehlman and Youle, 2020). This was associated with the enhanced formation of phospho-ubiquitin and K63 chain linkages in mouse neuronal mitochondria (Figure 1D) which was also found to be increased 70-fold in human iNeurons upon mitochondrial depolarisation (Ordureau et al, 2020).…”

“…Autosomal recessive mutations in human PTEN-induced kinase 1 (PINK1) and the RING-IBR-RING (RBR) ubiquitin E3 ligase Parkin (encoded by PARK6 and PARK2 genes respectively) are causal for early-onset Parkinson’s disease (PD) (Kitada et al, 1998, Valente et al, 2004). Landmark cell-based studies have demonstrated that these proteins function within a common pathway to regulate stress-evoked mitophagy via a ubiquitin-dependent mechanism (Harper et al, 2018, Singh and Muqit, 2020, Moehlman and Youle, 2020). Upon loss of mitochondrial membrane potential that can be induced artificially by mitochondrial uncouplers (e.g.…”

Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth

“…The synuclein family contains three (α, β, and γ-synuclein) highly conserved, small, soluble membranebinding proteins 44 . α-Syn regulates membrane trafficking events 20,45 , whereas much less is known about the function of β-and γ-syn. These proteins are highly expressed in brain and to a lesser extent in other tissues 46 .…”

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

“…Rab GTPases are master regulators of vesicular trafficking and thus ideally placed to regulate and influence auto-lysosomal pathways [ 87 ]. Their interaction with LRRK2 has been extensively reviewed recently [ 89 , 111 , 112 ]. Notably, LRRK2 has been shown to phosphorylate Rab12 [ 110 , 113 ] and SQSTM1/p62 in vitro [ 114 ].…”