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15 giugno 2022



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

Ludovica Iovino, Veronica Giusti, Francesca Pischedda, Elena Giusto, Nicoletta Plotegher, Antonella Marte, Ilaria Battisti, Angela Di Iacovo, Algerta Marku, Giovanni Piccoli, Rina Bandopadhyay, Carla Perego, Tiziana Bonifacino, Giambattista Bonanno, Cristina Roseti, Elena Bossi, Giorgio Arrigoni, Luigi Bubacco, Elisa Greggio, Sabine Hilfiker & Laura Civiero


Acta Neuropathologica

Selezionato dal lettore: Dott. Lorenzo Fontanelli


Motivation: In this article Iovino et al propose a pathogenetic mechanism of the LRRK2 G2019S mutation, which is linked to late-onset familial Parkinson’s disease.

Using human caudate and putamen tissues from a Brain Bank, as well as from animal tissues (LRRK2 wild-type and LRRK2 G2019S knock-in homozygous mice), Authors found severe deficits in excitatory amino acid transporter (EAAT)-2 - one of the major glutamate transporters, expressed predominantly in astroglial cells, and responsible for about 90% of glutamate uptake – in LRRK2 PD patients. Along with a reduction of EEAT-2, expression levels of GFAP were significantly increased in patients’ tissues, indicating a increase in gliosis. In line with results in human tissues, Authors compared the expression of Glt-1 - the mouse equivalent of EAAT2 - in the striatum of LRRK2 WT and LRRK2 G2019S knock-in mice, finding consistent results. They also investigate how the mutation impacts EAAT2 electrophysiological properties by means of Xenopus laevis oocytes, observing a reduction in the inward EEAT transport-associated-current in the oocytes injected with LRRK2 G2019S mRNA, compared to the one injected with LRRK2 WT mRNA. They further obtained fluorescence images of EEAT2, demonstrating that, compared to controls, where the protein is mainly localized at the plasma, in the oocytes expressing LRRK2 G2019S it was indeed sparsely localized. Of note, the effects of G2019S LRRK2 on EAAT2 were restored upon acute inhibition of the G2019S kinase activity by MLi-2, indicating that pathogenic LRRK2 impairs proper EAAT2 homeostasis. Performing ultrastructural analysis, Authors found that the LRRK2 G2019S mutation alters the architecture of the fast-recycling Rab4-positive organelles in astrocytes and that overexpression of active Rab8/Rab10 in LRRK2 G2019S astrocytes restored the dimension of the Rab4-positive vesicles, pointing to the LRRK2-mediated phosphorylation and inactivation of Rab8A/Rab10 as the pathogenic mechanism causing the Glt-1 trafficking defects in these cells.
Authors provides convincing evidences that a chronic LRRK2-mediated impairment of the recycling machinery in brain cells might cause a depletion of Glt-1 with a consequent reduction of extracellular glutamate clearance that leads to progressive neuronal damage.
Deep understanding of pathogenetic mechanism of genetic polymorphism is of uttermost importance in evaluating new therapeutic approaches.




Genetic Architecture of Stroke of Undetermined Source: Overlap with Known Stroke Etiologies and Associations with Modifiable Risk Factors


Marios K Georgakis, Livia Parodi, Simon Frerich, Ernst Mayerhofer, Georgios Tsivgoulis, James P. Pirruccello, Agnieszka Slowik, Tatjana Rundek, Rainer Malik,Martin Dichgans, Jonathan Rosand, Christopher D. Anderson,NINDS Stroke Genetics Network (SiGN) 

 Ann Neurol. 2022 May;91(5):640-651. doi: 10.1002/ana.26332 

Selezionato dal lettore: Dott. Matteo Farè


Motivation: Currently, about 30% of ischemic stroke cases have no identified cause, but it is hypothesized that these strokes result from emboli of non-stenosing atherosclerotic lesions, from cardioemboli during unknown atrial fibrillation, or from paradoxical emboli in the presence of PFO. 
Using a Genome-Wide Association Study (GWAS) method, this study aims to evaluate the role in strokes with undetermined source of genetic polymorphisms, which are already known to play a role as risk factors in LAAS (Large-Artery Atherosclerotic Strokes), CES (Cardio-Embolic Strokes) and SVS (Small Vessel Strokes). The data were extracted from the international NINDS registry, from which clinical data on 16. 851 strokes, classified according to TOAST and CCS, including 4,755 strokes with undetermined source, and on 32,473 healthy controls. 
19 loci were identified in common with LAAS, 2 with CES, and 5 with SVS, generally associated with mechanisms of thrombosis, atherosclerosis, or vascular risk factors. Using Mendelian randomization, associations were identified between stroke of undetermined source and carotid atherosclerosis, but also with loci usually associated with diabetes, obesity, hypertension, and pro-inflammatory and/or pro-coagulant mechanisms (IL-6, MCP-1, XI factor). 
Despite the limitations of the current in-use etiologic classifications (TOAST, CCS), with an extremely large sample this study emphasized that strokes with indeterminate source share the main risk factors, genetic and environmental, of other strokes, also allowing the hypothesis of additional pathophysiologic mechanisms, including inflammation and coagulation pathways, on which to potentially devise new targeted drugs or clinical studies. 
























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