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  1. Article ; Online: splitGFP Technology Reveals Dose-Dependent ER-Mitochondria Interface Modulation by α-Synuclein A53T and A30P Mutants

    Tito Calì / Denis Ottolini / Mattia Vicario / Cristina Catoni / Francesca Vallese / Domenico Cieri / Lucia Barazzuol / Marisa Brini

    Cells, Vol 8, Iss 9, p

    2019  Volume 1072

    Abstract: 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 ...

    Abstract 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 Ca 2+ 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 Ca 2+ handling and mitochondrial function using a newly generated SPLICS sensor and aequorin-based Ca 2+ 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 Ca 2+ 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 Ca 2+ cross-talk impairment to the pathogenesis of PD.
    Keywords Parkinson’s disease ; alpha-synuclein ; calcium ; mitochondria ; ER-mitochondria contact sites ; Biology (General) ; QH301-705.5
    Subject code 333
    Language English
    Publishing date 2019-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Generation and validation of novel adeno-associated viral vectors for the analysis of Ca2+ homeostasis in motor neurons

    Rosa Pia Norante / Maria Lina Massimino / Paolo Lorenzon / Agnese De Mario / Caterina Peggion / Mattia Vicario / Mattia Albiero / Maria Catia Sorgato / Raffaele Lopreiato / Alessandro Bertoli

    Scientific Reports, Vol 7, Iss 1, Pp 1-

    2017  Volume 11

    Abstract: Abstract A finely tuned Ca2+ homeostasis in restricted cell domains is of fundamental importance for neurons, where transient Ca2+ oscillations direct the proper coordination of electro-chemical signals and overall neuronal metabolism. Once such a ... ...

    Abstract Abstract A finely tuned Ca2+ homeostasis in restricted cell domains is of fundamental importance for neurons, where transient Ca2+ oscillations direct the proper coordination of electro-chemical signals and overall neuronal metabolism. Once such a precise regulation is unbalanced, however, neuronal functions and viability are severely compromised. Accordingly, disturbed Ca2+ metabolism has often been claimed as a major contributor to different neurodegenerative disorders, such as amyotrophic lateral sclerosis that is characterised by selective motor neuron (MN) damage. This notion highlights the need for probes for the specific and precise analysis of local Ca2+ dynamics in MNs. Here, we generated and functionally validated adeno-associated viral vectors for the expression of gene-encoded fluorescent Ca2+ indicators targeted to different cell domains, under the transcriptional control of a MN-specific promoter. We demonstrated that the probes are specifically expressed, and allow reliable local Ca2+ measurements, in MNs from murine primary spinal cord cultures, and can also be expressed in spinal cord MNs in vivo, upon systemic administration to newborn mice. Preliminary analyses using these novel vectors have shown larger cytosolic Ca2+ responses following stimulation of AMPA receptors in the cytosol of primary cultured MNs from a murine genetic model of ALS compared to the healthy counterpart.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2017-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

    Roberto Costa / Roberta Peruzzo / Magdalena Bachmann / Giulia Dalla Montà / Mattia Vicario / Giulia Santinon / Andrea Mattarei / Enrico Moro / Rubén Quintana-Cabrera / Luca Scorrano / Massimo Zeviani / Francesca Vallese / Mario Zoratti / Cristina Paradisi / Francesco Argenton / Marisa Brini / Tito Calì / Sirio Dupont / Ildikò Szabò /
    Luigi Leanza

    Cell Reports, Vol 28, Iss 8, Pp 1949-1960.e

    2019  Volume 6

    Abstract: Summary: Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondrial energetic state affects Wnt signaling is ... ...

    Abstract Summary: Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondrial energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/β-catenin signaling in vitro in colon cancer cells and in vivo in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondrial ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondrial energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologies. : Wnt signaling and mitochondrial fitness are both important for cell fate. Costa et al. demonstrate that the reduction of mitochondrial ATP production leads to the induction of ER stress and, in turn, decreases canonical Wnt/β-catenin signaling in vitro and in vivo. Keywords: mitochondrial fitness, mitochondrial ATP, canonical Wnt signaling, β-catenin, ER stress, colon cancer, SERCA
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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