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

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.

Surface GluA1 and glutamatergic transmission are increased in cortical neurons of a VPS35 D620N knock-in mouse model of parkinsonism and altered by LRRK2 kinase inhibition

“…LRRK2 kinase inhibition affects post-synaptic AMPAR trafficking in all genotypes, including WT, but has no apparent effect on presynaptic mutant Pr, suggesting caution is necessary in the wide application of LRRK2 kinase inhibitor treatment for PD. We add support to the theory that synaptic transmission is augmented at early time points in PD, which potentially represents early pathophysiological processes that can be targeted to prevent transition to later pathological damage (reviewed in Kuhlmann & Milnerwood, 2020; Picconi, Piccoli, & Calabresi, 2012; Volta, Milnerwood, & Farrer, 2015).…”

“…Increased autophosphorylation of LRRK2 and phosphorylation of Rab10 have been observed in post-mortem substantia nigra from individuals with idiopathic PD (Di Maio et al, 2018), monocytes from humans with the D620N mutation, and tissues from VPS35 D620N knock-in mice (Mir et al, 2018). This provides evidence that VPS35 and LRRK2 mutations converge on LRRK2 kinase, and that aberrant phosphorylation of Rab proteins involved in synaptic transmission may be related to synaptic phenotypes observed in PD models (reviewed in Kuhlmann & Milnerwood, 2020).…”

Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

“…There are outstanding reviews on the role of LRRK2 at the synapse (Nguyen et al, 2019 ; Pan et al, 2019 ; Kuhlmann and Milnerwood, 2020 ; Mancini et al, 2020 ). Our goal here is to focus on which synapses in the brain LRRK2 may be acting.…”

“…In the brain, LRRK2 is expressed in glutamatergic pyramidal neurons of the cortex ( Figure 2 ), and GABAergic SPNs of the striatum, particularly in the striosome compartment (West et al, 2014 ). Studies of LRRK2 expression in dopamine neurons of the SNc have produced variable results (Kuhlmann and Milnerwood, 2020 ): LRRK2 is expressed in dopamine neurons of the SNc in the mouse brain, but is not expressed, or has low levels of expression in the SNc in the rat brain (West et al, 2014 ). The expression of LRRK2 in the SNc of the human brain has yet to be confirmed.…”

Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein

“…LRRK2 and α -synuclein are highly expressed in excitatory neurons, [55]. LRRK2 kinase activity influences the physiological activity of excitatory neurons [55,58,75,76]. High expression levels and the presynaptic enrichment of α -synuclein at glutamatergic terminals may have crucial implications for glutamate transmission [77,78].…”