Abstract
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of dominant and sporadic Parkinson’s disease (PD), a common neurodegenerative disorder. Yeast-two-hybrid screening using human LRRK2 kinase domain as bait identified microtubule associated protein 1B (MAP1B) as a LRRK2 interactor. The interacting domains were LRRK2 kinase and the light chain portion of MAP1B (LC1). LRRK2 + LC1 interaction resulted in LRRK2 kinase inhibition. LRRK2 mutants (R1441C, G2019S and I2020T) exhibited decreased endogenous LC1 expression and its co-expression with LC1 rescued LRRK2 mutant-mediated toxicity. This study presented the first data on the effects of LRRK2 + LC1 interaction and also suggested that LCI possibly rescued LRRK2 mutant-induced cytotoxicity by inhibiting LRRK2 kinase activity. Compounds that upregulate LC1 expression may therefore hold therapeutic potential for LRRK2-linked diseases.
Highlights
Parkinson’s disease (PD), a neurodegenerative disorder, has been estimated to afflict six million people worldwide [1,2] and mutations in the leucine-rich repeat kinase 2 (LRRK2) gene is the most common cause of dominant and sporadic PD [3,4]
LRRK2 + light chain portion of MAP1B (LC1) interaction was further supported when purified LC1-GST protein successfully pulled down the LRRK2 kinase domain that was overexpressed in SKNSH (Additional file 1: Figure S2)
microtubuleassociated protein 1B (MAP1B) was identified as a LRRK2 interactor through yeast-two-hybrid screening using human LRRK2 kinase domain as bait; the interacting domains were narrowed down to the LRRK2 kinase and LC1
Summary
Parkinson’s disease (PD), a neurodegenerative disorder, has been estimated to afflict six million people worldwide [1,2] and mutations in the leucine-rich repeat kinase 2 (LRRK2) gene is the most common cause of dominant and sporadic PD [3,4]. Common pathogenic LRRK2 mutations like R1441C/G, Y1699C, G2019S and I2020T reside within the Roc-COR-kinase domains and are associated with increased kinase activity, which is in turn linked to increased neurotoxicity [5,6]. Though the enzymatic functions of LRRK2 have been extensively studied, its physiological mechanism remains unknown. LRRK2 was reported to phosphorylate and negatively regulate Futsch, the fly homolog of microtubuleassociated protein 1B (MAP1B), at the pre-synapse [7]. LC1 has been reported to dimerize or oligomerize [9] and its overexpression can lead to endoplasmic reticulum stress-induced apoptosis [10]
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