Elevated levels of alpha-synuclein blunt cellular signal transduction downstream of Gq protein-coupled receptors

Volta, Mattia; Lavdas, Alexandros A.; Obergasteiger, Julia; Überbacher, Christa; Picard, Anne; Pramstaller, Peter P.; Hicks, Andrew A.; Corti, Corrado

doi:10.1016/j.cellsig.2016.11.012

Cited by 9 publications

(4 citation statements)

References 62 publications

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“…There are now six different families of PLC (β, γ, δ, 𝜀, ζ, and η) described in different tissues, with pleiotropic functions associated with the membrane receptor to which they are coupled (Kadamur and Ross, 2013). It has recently been shown that α-synuclein overexpression interferes with Gq/PLC-β signaling by preventing the rise in cytosolic calcium and ERK 1/2 activation (Volta et al, 2017). α-Synuclein is also able to trigger the impairment of G-protein signaling associated with sphingosine-1-phosphate by promoting the exclusion of the receptor from lipid rafts (Mohamed Badawy et al, 2018).…”

Section: α-Synuclein and Lipid Signalingmentioning

confidence: 99%

Lipids at the Crossroad of α-Synuclein Function and Dysfunction: Biological and Pathological Implications

Alza

González

Conde

et al. 2019

Front. Cell. Neurosci.

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Since its discovery, the study of the biological role of α-synuclein and its pathological implications has been the subject of increasing interest. The propensity to adopt different conformational states governing its aggregation and fibrillation makes this small 14-kDa cytosolic protein one of the main etiologic factors associated with degenerative disorders known as synucleinopathies. The structure, function, and toxicity of α-synuclein and the possibility of different therapeutic approaches to target the protein have been extensively investigated and reviewed. One intriguing characteristic of α-synuclein is the different ways in which it interacts with lipids. Though in-depth studies have been carried out in this field, the information they have produced is puzzling and the precise role of lipids in α-synuclein biology and pathology and vice versa is still largely unknown. Here we provide an overview and discussion of the main findings relating to α-synuclein/lipid interaction and its involvement in the modulation of lipid metabolism and signaling.

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Section: α-Synuclein and Lipid Signalingmentioning

confidence: 99%

Lipids at the Crossroad of α-Synuclein Function and Dysfunction: Biological and Pathological Implications

Alza

González

Conde

et al. 2019

Front. Cell. Neurosci.

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“…SK-N-SH neuroblastoma cell lines stably overexpressing A35T-aSyn were recently described and maintained as in ref. 87 . HEK293T cells were grown in culture medium composed of MEM supplemented with 10% FBS, 1% MEM non-essential amino acids, 1% L-Glutamine, 1% P/S.…”

Section: Methodsmentioning

confidence: 99%

“…Cell culture and transfection SH-SY5Y neuroblastoma cell lines stably overexpressing wild-type (WT) or G2019S-LRRK2 were previously described 86,87 and maintained as in ref. 38 .…”

Section: Methodsmentioning

confidence: 99%

The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology

Obergasteiger

Castonguay

Pizzi

et al. 2023

npj Parkinsons Dis.

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In Parkinson’s disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear, but they are hypothesized to involve the autophagy-lysosome pathway (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, and LRRK2 kinase activity has been shown to be involved in pS129-aSyn inclusion modulation. We observed selective downregulation of the novel PD risk factor RIT2 in vitro and in vivo. Rit2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions. In vivo, viral mediated overexpression of Rit2 operated neuroprotection against AAV-A53T-aSyn. Furthermore, Rit2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo. On the other hand, reduction of Rit2 levels leads to defects in the ALP, similar to those induced by the G2019S-LRRK2 mutation. Our data indicate that Rit2 is required for correct lysosome function, inhibits overactive LRRK2 to ameliorate ALP impairment, and counteracts aSyn aggregation and related deficits. Targeting Rit2 could represent an effective strategy to combat neuropathology in familial and idiopathic PD.

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“…SH-SY5Y neuroblastoma cell lines stably overexpressing wild-type (WT) or G2019S-LRRK2 were previously described (Obergasteiger et al, 2017; Vancraenenbroeck et al, 2014) and maintained as in(Obergasteiger et al, 2020). SK-N-SH neuroblastoma cell lines stably overexpressing A35T-aSyn were recently described and maintained as in (Volta et al, 2017). Cells were transfected using the SF Cell Line 4D-Nucleofector™ X kit (Lonza) with the 4D Nucleofector X unit.…”

Section: Methodsmentioning

confidence: 99%

RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology

Obergasteiger

Castonguay

Frapporti

et al. 2020

Preprint

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In Parkinson's disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear but hypothesized to involve the autophagy lysosome pathways (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, hyperactivate kinase activity and its pharmacological inhibition reduces pS129-aSyn inclusions. We observed selective downregulation of the novel PD risk factor RIT2 in G2019S-LRRK2 expressing cells. Here we studied whether RIT2 could modulate LRRK2 kinase activity. RIT2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions. In vivo, viral mediated overexpression of RIT2 operated neuroprotection against AAV-A53T-aSyn. Furthermore, RIT2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo. Our data indicate that RIT2 inhibits overactive LRRK2 to ameliorate ALP impairment and counteract aSyn aggregation and related deficits. Targeting RIT2 could represent a novel strategy to combat neuropathology in familial and idiopathic PD.

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Elevated levels of alpha-synuclein blunt cellular signal transduction downstream of Gq protein-coupled receptors

Cited by 9 publications

References 62 publications

Lipids at the Crossroad of α-Synuclein Function and Dysfunction: Biological and Pathological Implications

Lipids at the Crossroad of α-Synuclein Function and Dysfunction: Biological and Pathological Implications

The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology

RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology

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