A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2.

Naila Kuhlmann,Austen J Milnerwood

doi:10.3389/fnmol.2020.00153

Abstract

Since the discovery of LRRK2 mutations causal to Parkinson’s disease (PD) in the early 2000s, the LRRK2 protein has been implicated in a plethora of cellular processes in which pathogenesis could occur, yet its physiological function remains elusive. The development of genetic models of LRRK2 PD has helped identify the etiological and pathophysiological underpinnings of the disease, and may identify early points of intervention. An important role for LRRK2 in synaptic function has emerged in recent years, which links LRRK2 to other genetic forms of PD, most notably those caused by mutations in the synaptic protein α-synuclein. This point of convergence may provide useful clues as to what drives dysfunction in the basal ganglia circuitry and eventual death of substantia nigra (SN) neurons. Here, we discuss the evolution and current state of the literature placing LRRK2 at the synapse, through the lens of knock-out, overexpression, and knock-in animal models. We hope that a deeper understanding of LRRK2 neurobiology, at the synapse and beyond, will aid the eventual development of neuroprotective interventions for PD, and the advancement of useful treatments in the interim.

Highlights

Reviewed by: Genta Ito, The University of Tokyo, Japan Tomoki Kuwahara, The University of Tokyo, Japan
Dopamine alterations from LRRK2 overexpression are accompanied by dysfunction at glutamate synapses; while there were no basal electrophysiological differences observed in evoked glutamate release onto striatal neurons, concomitant dopamine release negatively tuned glutamate release onto spiny projection neurons (SPNs) of human wild-type (hWT)-LRRK2 OE mice, an effect eliminated by presynaptic D2 receptor (D2R) blockade (Beccano-Kelly et al, 2015)
A direct effect of LRRK2 overexpression on the glutamatergic release is less clear: there were no basal differences in synaptic transmission in hippocampal slices from bacterial artificial chromosomes (BACs) hWT-LRRK2 OE mice compared to non-transgenic animals (Sweet et al, 2015), but cortical cultures show a small increase in synapse density and a non-significant trend to increased spontaneous release (Beccano-Kelly et al, 2014)

Summary

Introduction

Reviewed by: Genta Ito, The University of Tokyo, Japan Tomoki Kuwahara, The University of Tokyo, Japan. With emerging reports that LRRK2 functionally interacts with α-syn and other PD-linked proteins in axons and at the synapse (Lin et al, 2009; Inoshita et al, 2017; Mir et al, 2018; Novello et al, 2018; MacIsaac et al, 2020), therapeutic advancements may well depend on understanding how mutations in LRRK2 disrupt synaptic activity within the complex neural circuitry underlying PD.

Results

Conclusion