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splitGFP Technology Reveals Dose-Dependent ER-Mitochondria Interface Modulation by α-Synuclein A53T and A30P Mutants

1
Department of Biomedical Sciences, University of Padova, Padova 35131, Italy
2
Padova Neuroscience Center (PNC), University of Padova, Padova 35131, Italy
3
Department of Biology, University of Padova, Padova 35131, Italy
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(9), 1072; https://doi.org/10.3390/cells8091072
Received: 4 August 2019 / Revised: 9 September 2019 / Accepted: 11 September 2019 / Published: 12 September 2019
Familial Parkinson’s disease (PD) is associated with duplication or mutations of α-synuclein gene, whose product is a presynaptic cytosolic protein also found in mitochondria and in mitochondrial-associated ER membranes. We have originally shown the role of α-syn as a modulator of the ER-mitochondria interface and mitochondrial Ca2+ transients, suggesting that, at mild levels of expression, α-syn sustains cell metabolism. Here, we investigated the possibility that α-syn action on ER-mitochondria tethering could be compromised by the presence of PD-related mutations. The clarification of this aspect could contribute to elucidate key mechanisms underlying PD. The findings reported so far are not consistent, possibly because of the different methods used to evaluate ER-mitochondria connectivity. Here, the effects of the PD-related α-syn mutations A53T and A30P on ER-mitochondria relationship were investigated in respect to Ca2+ handling and mitochondrial function using a newly generated SPLICS sensor and aequorin-based Ca2+measurements. We provided evidence that A53T and A30P amino acid substitution does not affect the ability of α-syn to enhance ER/mitochondria tethering and mitochondrial Ca2+ transients, but that this action was lost as soon as a high amount of TAT-delivered A53T and A30P α-syn mutants caused the redistribution of α-syn from cytoplasm to foci. Our results suggest a loss of function mechanism and highlight a possible connection between α-syn and ER-mitochondria Ca2+ cross-talk impairment to the pathogenesis of PD. View Full-Text
Keywords: Parkinson’s disease; alpha-synuclein; calcium; mitochondria; ER-mitochondria contact sites Parkinson’s disease; alpha-synuclein; calcium; mitochondria; ER-mitochondria contact sites
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Calì, T.; Ottolini, D.; Vicario, M.; Catoni, C.; Vallese, F.; Cieri, D.; Barazzuol, L.; Brini, M. splitGFP Technology Reveals Dose-Dependent ER-Mitochondria Interface Modulation by α-Synuclein A53T and A30P Mutants. Cells 2019, 8, 1072.

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