Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease

Author:

Iovino LudovicaORCID,Giusti VeronicaORCID,Pischedda FrancescaORCID,Giusto ElenaORCID,Plotegher NicolettaORCID,Marte AntonellaORCID,Battisti Ilaria,Iacovo Angela Di,Marku AlgertaORCID,Piccoli GiovanniORCID,Bandopadhyay RinaORCID,Perego CarlaORCID,Bonifacino TizianaORCID,Bonanno GiambattistaORCID,Roseti CristinaORCID,Bossi ElenaORCID,Arrigoni GiorgioORCID,Bubacco LuigiORCID,Greggio ElisaORCID,Hilfiker SabineORCID,Civiero LauraORCID

Abstract

AbstractThe Excitatory Amino Acid Transporter 2 (EAAT2) accounts for 80 % of brain glutamate clearance and is mainly expressed in astrocytic perisynaptic processes. EAAT2 function is finely regulated by endocytic events, recycling to the plasma membrane and degradation. Noteworthy, deficits in EAAT2 have been associated with neuronal excitotoxicity and neurodegeneration. In this study, we show that EAAT2 trafficking is impaired by the leucine-rich repeat kinase 2 (LRRK2) pathogenic variant G2019S, a common cause of late-onset familial Parkinson’s disease (PD). In LRRK2 G2019S human brains and experimental animal models, EAAT2 protein levels are significantly decreased, which is associated with elevated gliosis. The decreased expression of the transporter correlates with its reduced functionality in mouse LRRK2 G2019S purified astrocytic terminals and in Xenopus laevis oocytes expressing human LRRK2 G2019S. In Lrrk2 G2019S knockin mouse brain, the correct surface localization of the endogenous transporter is impaired, resulting in its interaction with a plethora of endo-vesicular proteins. Mechanistically, we report that pathogenic LRRK2 kinase activity delays the recycling of the transporter to the plasma membrane, causing its intracellular relocalization and degradation. Taken together, our results demonstrate that pathogenic LRRK2 interferes with the physiology of EAAT2, pointing to extracellular glutamate overload as a possible contributor to neurodegeneration in PD.

Publisher

Cold Spring Harbor Laboratory

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