LRRK2 at the Crossroad Between Autophagy and Microtubule Trafficking

Abstract

Mutations in leucine-rich repeat kinase 2 ( lrrk2) gene cause inherited Parkinson's disease (PD), and common variants in lrrk2 are a risk factor for sporadic PD. The neuropathology associated with LRRK2-linked PD is extremely pleomorphic involving inclusions of α-synuclein (SNCA), tau or neither, therefore suggesting that LRRK2 may be central in the pathogenic pathways of PD. This large protein localizes in the cytosol, as well as, in specific membrane domains, including mitochondria and autophagosomes and interacts with a wide range of proteins such as SNCA, tau, α- and β-tubulin. For this reason LRRK2 has been associated with a variety of cellular functions, including autophagy, mitochondrial function/dynamics and microtubule/cytoskeletal dynamics. LRRK2 has been shown to interact with microtubules as well as with mitochondria interfering with their network and dynamics. Moreover, LRRK2 knock-out or mutations affect autophagic efficiency. Here, we review and discuss the literature on how LRRK2 affects mitochondrial function, autophagy, and microtubule dynamics and how this is implicated in the PD etiology.

Increased Oxidative Stress Markers in Cerebrospinal Fluid from Healthy Subjects with Parkinson’s Disease-Associated LRRK2 Gene Mutations

“…The role of LRRK2 protein is incompletely understood; it possesses kinase and GTPase activities, and has been associated with autophagy, mitochondrial functions, and microtubule/cytoskeletal dynamics (Wallings et al, 2015; Esteves and Cardoso, 2016; Kang and Marto, 2016). Expression of the most common PD-associated LRRK2 mutation, G2019S (Kachergus et al, 2005), may uncouple mitochondrial oxidative phosphorylation (Mortiboys et al, 2010; Papkovskaia et al, 2012) and increase intracellular ROS production in vitro (Pereira et al, 2014).…”

68 and FX2149 Attenuate Mutant LRRK2-R1441C-Induced Neural Transport Impairment

“…Mutant LRRK2 has been shown to cause lysosome/autophagic pathway impairment (Alegre-Abarrategui and Wade-Martins, 2009; Henry et al, 2015; Esteves and Cardoso, 2016). A recent study has identified that LRRK2 mutations lead to an increase in lysosomal size and a decrease in their ability for degradation (Bandyopadhyay et al, 2014), as well as impairs the autophagic cycle's ability to clear toxic proteins (Alegre-Abarrategui and Wade-Martins, 2009; Esteves and Cardoso, 2016).…”

“…A recent study has identified that LRRK2 mutations lead to an increase in lysosomal size and a decrease in their ability for degradation (Bandyopadhyay et al, 2014), as well as impairs the autophagic cycle's ability to clear toxic proteins (Alegre-Abarrategui and Wade-Martins, 2009; Esteves and Cardoso, 2016). A functioning axonal transport system is necessary for the lysosome/autophagic pathway, as coordinated lysosome and autophagosome positioning and recruitment are prerequisites (Amaya et al, 2015).…”

“…These results demonstrate that mutant LRRK2 disruption of lysosomal transport is one of the early events in neuritic injury. LRRK2 has been implicated as a crossroad for the autophagic clearance of mitochondria (mitophagy) (Saez-Atienzar et al, 2014; Esteves and Cardoso, 2016). PD-linked LRRK2 mutations can cause a loss of mitochondrial membrane potential, which precedes elimination by mitophagy, thereby resulting in a decrease in available mitochondria for energy requirements (Su et al, 2015).…”

The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained

“…The diverse functional roles of LRRK2 have been under recent and extensive investigation. LRRK participates in the regulation of mitochondrial function, autophagy, and cytoskeletal dynamics (41). Most relevant to the topic of this review, LRRK2 has been shown to regulate calcium release from lysosomes through NAADP-receptors (42).…”