AUTHOR=Kuhlmann Naila , Milnerwood Austen J. 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 13 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2020.00153

DOI=10.3389/fnmol.2020.00153

ISSN=1662-5099

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 have helped identify the etiological and pathophysiological underpinnings of PD, and may identify early points of intervention. An important role for LRRK2 in synaptic function has emerged in recent years, which link LRRK2 to other genetic forms of PD, notably those causing mutations in the synaptic protein -synuclein. This point of convergence may provide useful clues as to what drives dysfunction in the basal ganglia circuitry, and eventual death of 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. Our hope is 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.