LRRK2 links genetic and sporadic Parkinson's disease

Abstract

The past two decades in research has revealed the importance of leucine-rich repeat kinase 2 (LRRK2) in both monogenic and sporadic forms of Parkinson's disease (PD). In families, mutations in LRRK2 can cause PD with age-dependent but variable penetrance and genome-wide association studies have found variants of the gene that are risk factors for sporadic PD. Functional studies have suggested that the common mechanism that links all disease-associated variants is that they increase LRRK2 kinase activity, albeit in different ways. Here, we will discuss the roles of LRRK2 in areas of inflammation and vesicular trafficking in the context of monogenic and sporadic PD. We will also provide a hypothetical model that links inflammation and vesicular trafficking together in an effort to outline how these pathways might interact and eventually lead to neuronal cell death. We will also highlight the translational potential of LRRK2-specific kinase inhibitors for the treatment of PD.

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson’s Disease

“…LRRK2 is an enzymatic protein involved in multiple cellular functions including neuronal outgrowth, cytoskeletal organization, mitochondrial dynamics, autophagy, protein interactions, and vesicle trafficking (Shin et al, 2008;Cirnaru et al, 2014;Piccoli et al, 2014;Arranz et al, 2015;Roosen and Cookson, 2016). Importantly, more recent reports have shown that LRRK2 is highly expressed in both brain and peripheral immune cells, playing a pivotal role in regulating the neuroinflammatory responses via the modulation of nuclear factor (NF)-kB pathway (Gardet et al, 2010;Hakimi et al, 2011;Thevenet et al, 2011;Moehle et al, 2012;Kluss et al, 2019). Notably, NF-kB is central to the efficacious actions of POM in multiple myeloma (Offidani et al, 2014).…”

Initiation and propagation of α-synuclein aggregation in the nervous system

“…Mutations in other genes linked to PD may also impact α-synuclein expression levels. For example, dominant inherited mutations in leucine-rich repeat kinase 2 (LRRK2) cause PD [96]. Additionally, neurons from BAC transgenic mice expressing the G2019S-LRRK2 mutations have higher total levels of cytosolic α-synuclein which could account for the increased fibril-induced α-synuclein aggregates found in mutant LRRK2 expressing mice [97].…”

Pathogenic mutations in LRRK2 sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

“…LRRK2 is a multidomain enzyme and PDlinked mutations are localized to its enzymatic domains, namely the kinase domain and Ras of complex proteins and C-terminal of ROC (ROC-COR) domains. LRRK2 has been linked to a number of cellular pathways including autophagy, lysosomal processing, inflammation and vesicular trafficking (4). LRRK2 is expressed in immune cells and reports suggest a role in microglial activation and an effect of PD-linked mutations on cytokine release and inflammation (5)(6)(7).…”

“…LRRK2 is expressed in immune cells and reports suggest a role in microglial activation and an effect of PD-linked mutations on cytokine release and inflammation (5)(6)(7). The kinase activity of LRRK2 is thought to drive pathology in disease, and thus is being targeted pharmacologically as a possible therapy (4).…”