Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson's disease

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene comprise the most common cause of familial Parkinson's disease (PD), and variants increase the risk for sporadic PD. LRRK2 displays kinase and GTPase activity, and altered catalytic activity correlates with neurotoxicity, making LRRK2 a promising therapeutic target. Despite the importance of LRRK2 for disease pathogenesis, its normal cellular function, and the mechanism(s) by which pathogenic mutations cause neurodegeneration remain unclear. LRRK2 seems to regulate a variety of intracellular vesicular trafficking events to and from the late endosome in a manner dependent on various Rab proteins. At least some of those events are further regulated by LRRK2 in a manner dependent on two-pore channels (TPCs). TPCs are ionic channels localized to distinct endosomal structures and can cause localized calcium release from those acidic stores, with downstream effects on vesicular trafficking. Here, we review current knowledge about the link between LRRK2, TPC- and Rab-mediated vesicular trafficking to and from the late endosome, highlighting a possible cross-talk between endolysosomal calcium stores and Rab proteins underlying pathomechanism(s) in LRRK2-related PD.

Endolysosomal degradation of Tau and its role in glucocorticoid‐driven hippocampal malfunction

“…Indeed, proteasome and lysosome inhibitors can delay Tau turnover and promote Tau-driven neuropathology (Zhang et al, 2005;Hamano et al, 2008). However, dysfunction of a third degradative pathway, the endolysosomal system, is also linked to AD and other neurodegenerative conditions that exhibit Tau accumulation, including Parkinson's disease (Rivero-Rios et al, 2015;Kett & Dauer, 2016;Small et al, 2017). Nevertheless, the role of the endolysosomal pathway in the clearance of Tau is almost completely unexplored.…”

Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice

“…LRRK2 is implicated in vesicular trafficking (16–19), perhaps owing to phosphorylation of Rab GTPases, key regulators in membrane trafficking (9,20). LRRK2 is also involved in the regulation of cytoskeletal dynamics (21–24), including an interaction with β-tubulin isoforms (21).…”

Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction

“…Indeed, proteasome and lysosome inhibitors can delay Tau turnover and promote Tau-driven neuropathology 18,19 . However, dysfunction of a third degradative pathway, the endo-lysosomal system, is also linked to AD and other neurodegenerative conditions that exhibit Tau accumulation, including Parkinson's disease [20][21][22] . Nevertheless, the role of the endo-lysosomal pathway in the clearance of Tau is almost completely unexplored.…”