The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

Abstract

Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α‐synuclein and LRRK2 pathogenic mutations. While α‐synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual‐enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α‐synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α‐synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14‐3‐3s that may regulate α‐synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α‐synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD.

Mechanisms and roles of mitophagy in neurodegenerative diseases

“…The toxicity of α‐Syn may also be mediated through its interaction with LRRK2 kinase. Common protein interactors may regulate or mediate α‐Syn and LRRK2 interaction in PD …”

LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation

“…Interestingly, we noticed the presence of a peculiar LC3 staining pattern in nigra, cortex, and hippocampus of hG2091S mice suggesting the presence of perinuclear pale bodies (supplementary figure 1). It has been suggested that LRRK2 mutations promote α-synuclein aggregation (Cresto et al 2019;MacIsaac et al 2020). Therefore we studied the distribution of α-synuclein in different brain areas of 6-month old wild-type and hG2019S mice.…”

The C-terminal fragment of LRRK2 with the G2019S substitution increases the neurotoxicity of mutant A53T α-synuclein in dopaminergic neurons in vivo

“…The cases of patients harboring the G2019S and other mutations are clinically indistinguishable from idiopathic PD cases, including the presence of Lewy bodies (LBs) in most cases [14,15]. Although G2019S patients show similar clinical manifestations as those of sporadic patients [16], several studies have shown subtle differences [17,18]. Some have reported the presence of LBs in symptomatic LRRK2 mutation carriers and LRRK2 can be found in LBs [19], although this is still a subject of debate, as other neuropathological studies have instead reported the absence of detectable LBs in a sub-population of PD patients with LRRK2 mutations [20].…”

“…The central role of α-syn in PD pathogenesis has led to the hypothesis of a functional (and possibly physical) interaction between LRRK2 and α-syn [for a review [25]. Indeed, LRRK2 toxicity may require the presence of α-syn and, conversely, the presence of variant/mutant LRRK2 could increase the risk and/or impact of α-synucleopathy in PD.…”

“…However, the mechanisms underlying the "protoxic" effect of LRRK2 (especially the G2019S mutation) on α-syn toxicity are not known and the exact role of the kinase domain has not been completely demonstrated. Pharmacological intervention suggests that the kinase activity of LRRK2 likely contributes to the synergy (for a review [16]). In addition, it is not known whether the potentiation of α-syn toxicity by the presence of LRRK2 G2019S is related solely to a cell-autonomous mechanism.…”