Abstract
Leucine-rich repeat kinase 2 is a large protein with implications in genetic and sporadic causes of Parkinson's disease. The physiological functions of LRRK2 are largely unknown. In this report, we investigated whether LRRK2 alters neural transport using live-cell imaging techniques and human neuroblastoma SH-SY5Y cells. Our results demonstrated that expression of the PD-linked mutant, LRRK2-R1441C, induced mitochondrial, and lysosomal transport defects in neurites of SH-SY5Y cells. Most importantly, recently identified GTP-binding inhibitors, 68 and FX2149, can reduce LRRK2 GTP-binding activity and attenuates R1441C-induced mitochondrial and lysosomal transport impairments. These results provide direct evidence and an early mechanism for neurite injury underlying LRRK2-induced neurodegeneration. This is the first report to show that LRRK2 GTP-binding activity plays a critical role during neurite transport, suggesting inhibition of LRRK2 GTP-binding could be a potential novel strategy for PD intervention.
Highlights
Parkinson’s disease (PD) is a common progressive neurodegenerative disease with movement disorder
Previous studies reported that the leucinerich repeat kinase 2 (LRRK2)-R1441 mutant causes disrupted neurite outgrowth, leads to decreased neuritic branching in PD models using cultured cell lines or primary neurons (MacLeod et al, 2006; Heo et al, 2010; Cherra et al, 2013; Tagliaferro et al, 2015)
We used SHSY5Y cells transiently transfected with Flag-wild-type and FlagR1441C-LRRK2 constructs as a cell model to express the LRRK2 variants
Summary
Parkinson’s disease (PD) is a common progressive neurodegenerative disease with movement disorder. The pathogenesis of PD is not completely clear, mutations in the leucinerich repeat kinase 2 (LRRK2) represent the most common known cause of PD to date (Klein and Lohmann-Hedrich, 2007; Paisán-Ruiz et al, 2013). LRRK2-associated PD cases have pleomorphic pathology, the physiological function of LRRK2 is largely undetermined. LRRK2 is a large 286 kDa cytoplasmic protein and contains several functional domains (Li et al, 2011). Studies suggest that LRRK2 is involved in multiple cellular processes, including cytoskeletal organization, neuronal outgrowth, mitochondrial dynamics, autophagy, endocytosis, and protein interactions (Mata et al, 2006; Raquel Esteves et al, 2014). PD-linked LRRK2 mutations cause neuronal degeneration the underlying mechanisms remain elusive
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