The 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 knock-in 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 via Rabs inactivation, causing its intracellular re-localization 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.

Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson's disease / L. Iovino, V. Giusti, F. Pischedda, E. Giusto, N. Plotegher, A. Marte, I. Battisti, A. Di Iacovo, A. Marku, G. Piccoli, R. Bandopadhyay, C. Perego, T. Bonifacino, G. Bonanno, C. Roseti, E. Bossi, G. Arrigoni, L. Bubacco, E. Greggio, S. Hilfiker, L. Civiero. - In: ACTA NEUROPATHOLOGICA. - ISSN 0001-6322. - 144:1(2022 Jul), pp. 81-106. [10.1007/s00401-022-02437-0]

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

A. Marku;C. Perego;
2022

Abstract

The 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 knock-in 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 via Rabs inactivation, causing its intracellular re-localization 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.
Astrocytes; EAAT2; Glia; Glt-1; LRRK2; Parkinson’s disease;
Settore BIO/09 - Fisiologia
lug-2022
21-mag-2022
Article (author)
File in questo prodotto:
File Dimensione Formato  
s00401-022-02437-0.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 13.11 MB
Formato Adobe PDF
13.11 MB Adobe PDF Visualizza/Apri
s00401-022-02437-0_compressed.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.17 MB
Formato Adobe PDF
1.17 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/929003
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 23
  • ???jsp.display-item.citation.isi??? 22
social impact