LRRK2 and α-Synuclein: Distinct or Synergistic Players in Parkinson's Disease?

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by prominent degeneration of dopaminergic neurons in the substantia nigra and aggregation of the protein α-synuclein within intraneuronal inclusions known as Lewy bodies. Ninety percent of PD cases are idiopathic while the remaining 10% are associated with gene mutations that affect cellular functions ranging from kinase activity to mitochondrial quality control, hinting at a multifactorial disease process. Mutations in LRRK2 and SNCA (the gene coding for α-synuclein) cause monogenic forms of autosomal dominant PD, and polymorphisms in either gene are also associated with increased risk of idiopathic PD. Although Lewy bodies are a defining neuropathological feature of PD, an appreciable subset of patients with LRRK2 mutations present with a clinical phenotype indistinguishable from idiopathic PD but lack Lewy pathology at autopsy, suggesting that LRRK2-mediated PD may occur independently of α-synuclein aggregation. Here, we examine whether LRRK2 and α-synuclein, as mediators of neurodegeneration in PD, exist in common or distinct pathways. Specifically, we review evidence from preclinical models and human neuropathological studies examining interactions between the two proteins. Elucidating the degree of interplay between LRRK2 and α-synuclein will be necessary for treatment stratification once effective targeted disease-modifying therapies are developed.

Keywords: LRRK2; Parkinson’s disease; autophagy; mitochondria; neurodegeneration; α-synuclein.

FIGURE 1

Potential ways in which LRRK2 and α-synuclein act in PD. (A) LRRK2 and α-synuclein affect each other through a direct physical interaction. (B) LRRK2 and α-synuclein affect each other through an indirect physical interaction in which a mediator(s), such as a molecular chaperone(s), links the two proteins. (C) Both LRRK2 and α-synuclein act synergistically on targets within the same molecular pathway without interacting with each other. (D) LRRK2 and α-synuclein do not interact at all and each affect targets in distinct molecular pathways.

FIGURE 2

Contribution of mutant LRRK2 to cell-to-cell transmission of α-synuclein. Increased kinase activity of mutant LRRK2 can phosphorylate Rab35 affecting its interaction with its substrates, and eventually preventing the endosome-lysosmal degradation of α-synuclein aggregates. This in turn can increase the mobile cytosolic pools of α-synuclein aggregate seeds which can get released into the extracellular space in exosomes. These seeds can then be taken up into the cytosol of neighboring neurons where they can promote aggregation of α-synuclein monomers into oligomers and fibrils.

FIGURE 3

Effects of LRRK2 and α-synuclein on the autophagy-lysosomal pathway. This is an example of how LRRK2 and α-synuclein can have convergent mechanisms with both affecting the autophagy-lysosomal system but each acting on different targets within the system. Mutant or aggregated α-synuclein can block CMA and autophagosome formation, while mutant LRRK2 can also block CMA, disrupt mitophagy or delay autophagosome trafficking.