The emerging role of LRRK2 in tauopathies

Abstract

Parkinson's disease (PD) is conventionally described as an α-synuclein aggregation disorder, defined by Lewy bodies and neurites, and mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common autosomal dominant cause of PD. However, LRRK2 mutations may be associated with diverse pathologies in patients with Parkinson's syndrome including tau pathology resembling progressive supranuclear palsy (PSP). The recent discovery that variation at the LRRK2 locus is associated with the progression of PSP highlights the potential importance of LRRK2 in tauopathies. Here, we review the emerging evidence and discuss the potential impact of LRRK2 dysfunction on tau aggregation, lysosomal function, and endocytosis and exocytosis.

Keywords: LRRK2; Parkinson's disease; Progressive Supranuclear Palsy; Tau.

Figure 1. Potential mechanisms by which LRRK2 could impact the development and progression of tau pathology

(A) LRRK2 could impact tau aggregation by phosphorylating tau directly, by binding to microtubules or by altering tau kinase or phosphatase activity. (B) LRRK2 affects lysosomal function by (1) impairing autophagosome biogenesis, (2) lysosomal fusion, or (3) lysosomal degradative capacity, thereby promoting tau cytoplasmic accumulation, aggregation, and spreading. (C) LRRK2 impacts on both endocytic and exocytic pathways, which could impact the recycling of tau receptors, or directly affect the intracellular trafficking of tau. Impaired intracellular trafficking could result in (1) decreased tau uptake, (2) increased cytoplasmic accumulation and aggregation, or (3) increased exocytosis. Structure of LRRK2 derived from PDB 7LHT using UCSF ChimeraX.