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Doctoral school

PhD in Neuroscience

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Dott.ssa Valentina Scarpetta

Contacts

Supervisor

Marco Sassoè

Phd thesis

Choroid Plexus structure and functions

The Choroid Plexus (ChP) is a highly vascularized structure located in the ventricular system of the brain, where it forms a selective interface between blood and cerebrospinal fluid (CSF). The ChP has a distinct tissue organization, which comprises an external monolayer of specialized epithelial cells, a connective stroma and a highly permeable fenestrated capillary network. Epithelial cells are interconnected by tight junctions (TJs) forming a permissive barrier called blood-CSF fluid barrier. ChP is mainly known for producing and secreting the majority of CSF. Recent studies demonstrate that ChP also modulates brain function by producing and releasing multiple nourishing factors, such active polypeptides and neuromodulators that can reach and act on the brain. 

To date, molecular mechanisms governing the secretory ability of the ChP are still largely unexplored. Recently it has been demonstrated that epithelial cells of the ChP own the calcium-dependent soluble NSF attachment receptor (SNARE) complex proteins. Interestingly, in the ChP this process is activated by serotonin-mediated stimulation of the 5-HT2C receptor (5-HT2RC) located on the CSF-facing apical surface of the cells, potentially leading to a general increased in the secretory activity of the epithelium or inducing the secretion of insulin or transferrin into the CSF. The 5-HT2RC is a Gq/G11-coupled G protein-coupled receptor (GPCR) able to activate the phospholipase C (PLC-β) enzyme and hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol trisphosphate (IP3). When IP3 is activated, it can act as a second messenger leading to the released of calcium stored into the cytoplasm. However, little is known about the role of calcium increase in regulating the secretion of selected proteins from the epithelium of the ChP. It is quite well accepted that CSF composition changes through aging and can be influenced by neuroinflammatory events, leading to drastic changes of the production of active nourishing factors, potentially leading to the decline of cognitive function. At the same time, age-related morphological modifications of the ChP, that could affect secretory function and/or CSF production, have been described during physiological aging. Our hypothesis is that both architectural modifications and interferon signaling can impact ChP secretome and composition of the CSF, further interfering with the physiological regulation of brain parenchyma.

Given the impact that deterioration of ChP morphology and functionality exerts on worsening neurodegenerative disorders, the aims of my PhD project are to investigate the age-related morphological modifications in the epithelial cells of the murine ChP. Moreover, consistent with the knowledge that the ChP secretory machinery can be dependent on calcium, I will study how the spontaneous intracellular calcium transients change during adulthood and whether their sensitivity to serotonin may be affected during aging.

MORPHOLOGIVAL AND MITOCHONDRIAL ALTERATIONS. Using electron microscopy, two-photon microscopy and biochemistry, we have investigated ChP epithelial cells during healthy aging, starting from young adult to two-years old mice. We identified distinct morpho-functional modifications in ChP epithelial cells in mice aged 8-12 months, which mostly remained stable up to two years. These changes include flattening of the epithelium, reduction of microvilli length, enlargement of basolateral membrane invaginations and augmentation of interrupted tight junctions. We also found a decrease in mitochondria density together with elongation of mitochondria in older mice. Two-photon imaging of whole ChP living explants revealed that morphological rearrangements of mitochondria were accompanied by increased superoxide levels, decreased membrane potential and decreased mitochondrial motility in aged mice, suggesting possible mitochondrial oxidative damage and impaired ability to synthetize ATP at baseline. Interestingly, most of the age-related changes were not accompanied by modification of protein and/or gene expression levels and aged mitochondria effectively responded to acute pharmacological stressful stimuli, raising the possibility that the morphological remodeling observed in mitochondria may represent an adaptive mechanism engaged by ChP epithelial cells to endure stressful events. Our study suggests a long-term progression of multiple morpho-functional features of the mouse choroid plexus epithelium during lifetime.

CALCIUM-DEPENDENT SECRETORY MACHINERY. The next step of my PhD project aims at investigating how aging can impact ChP functionality, and in particular the calcium-dependent secretory pathway. To better characterize this process, will analyze how calcium spontaneous transients change overtime. Then, I will measure whether the response to serotonin application is different throughout aging. Finally, I will investigate whether aging has an impact on the secretory ability of the ChP epithelium and whether the secretion of selective proteins of interest are linked to the activation of the serotonin-dependent signaling.

Understanding how ChP functionality changes during aging, potentially leading to changes in the ChP secretome, could help unraveling how ChP is able to impact the rest of the parenchyma through the regulation of CSF composition.

Research activities

 

PhD program of the German Cancer Research center (DKFZ), Heidelberg, Germany

  • Seminar Series - German Cancer Research Center, Heidelberg (DKFZ), Neuronal Signaling and Morphogenesis (A320), every other Wednesday.

  • Journal Club - German Cancer Research Center, Heidelberg (DKFZ), Neuronal Signaling and Morphogenesis (A320), every other Wednesday.

2023

  • 2nd Thesis Advisory Committee (TAC) meeting - Written report and oral presentation, March 31 2023. Investigating the effect of aging on choroid plexus epithelial cells morphology and serotonin-induced activation of secretion. 
    DKFZ Internal member: Dr. Aurelio Teleman (Cost center B140, Signal Transduction in Cancer and Metabolism)
    DKFZ External member: Dr. Carlos Bas Orth (University of Heidelberg, Faculty of Medicine)

  • "Canonical Wnt signalling in the oncogenesis of choroid plexus tumors", Kim Hoa Ho. IZN seminar, 08.03.2023

2022

  • "Structural and functional dynamics of astrocytic mitochondria in vivo", Felipe Bodaleo. IZN seminar, 26.10.2022

  • Visual communication of science - German Cancer Research Center (DKFZ), February 7-8th 2022

  • First Aid Course - German Cancer Research Center (DKFZ), May 2022

2021

  • 1st Thesis Advisory Committee (TAC) meeting - Written report and oral presentation, May 17 2021. FUNCTIONAL AND MORPHOLOGICAL ALTERATIONS IN THE CHOROID PLEXUS DURING AGING
    DKFZ Internal member: Dr. Aurelio Teleman (Cost center B140, Signal Transduction in Cancer and Metabolism)
    DKFZ External member: Dr. Carlos Bas Orth (University of Heidelberg, Faculty of Medicine)
  • PhD Initial Course - German Cancer Research Center (DKFZ), June 9-18th 2021

  • LAC Compliance Instruction (DKFZ Mandatory course), April 21, 2021
  • Introductory course on laboratory animal science: Biostatistics (DKFZ e-learning course), April 18, 2021

  • Progress in Cancer Research (PiCR) - (35 Lectures, every Thursday at 9 am), German Cancer Research Center, Heidelberg (DKFZ).

PhD program in Neuroscience, Department of Neuroscience, Turin

2023

  • "Neuromuscular disorders in the era of advanced therapies: new perspectives for clinical and transitional research" - T. Mongini, A. Brusco, F. Ricci, L. Gastaldi. - September 20th and 22nd 2023
  • "Choroid plexus: a new entry point to study the brain development" - Annarita Patrizi. PhD'S Seminar Cycle. May 30th 2023, Institute of Anatomy, Turin.

2021

  • "From neural cell excitability to brain circuit recording, visualization and manipulation" - F. Ferrini,B. Sacchetti,S. Bovetti, E. Hoxha. - Toolbox Course, February 1st - 4th - 8th - 11th 2021

  • "Basic Concepts of Statistics" - A. Ricotti - Toolbox Course,  January 25th - 26th 2021.

2020

  • PhD Journal Club 2020/2021.

  • "Introduction to Research methodology" - D. Romano - Toolbox Course, December 4th - 11th - 18th 2020.

  • "Clinical, methodological and theoretical aspects of Translational and Cognitive Neuroscience" - A. Berti, A. Chiò, M. Giustetto - Toolbox Course, November 27th 2020.

  • "Inaugurazione anno dottorale 2020-2021" - S.Geuna, A.Rizzuti - Meeting, November 5th 2020.

  • "Welcome Meeting for PhD Students XXXVI cycle" - M.Sassoè - Webinar, October 21st 2020.

  • European Choroid plexus scientific forum, 1st Edition. Heidelberg, 7-9th November 2023

 

  • Progress in Cancer Research Lecture (PiCR) moderator of 3 lectures: 
    Lecturer: Niels Halama, October 5, 2023
    Lecturer: Klaus Maier-Hein, October 26, 2023
    Lecturer: Dirk Jager, November 23, 2023

  • Summer school 2023: ORGANOIDS in next generation cancer research - August 31st, September 1st 2023

  • International reviewer evaluation of DKFZ Junior Group leaders - July 31, 2023. Flash talk presentation and poster, MORPHOLOGICAL AND MITOCHONDRIAL CHANGES IN MURINE CHOROID PLEXUS EPITHELIAL CELLS DURING HEALTHY AGING.
    Reviewers: Prof. Dr. Thomas Brabletz (Clinical-Molecular Biology Research Center (KMFZ)) and Prof. Dr. Rene Medema (Netherlands Cancer Institute).
     
  • TRN MINDS Campus Day on Metabolism - BioQuant, Heidelberg, November 10th 2021

  • Mouse Surgery Module - German Cancer Research Center, Heidelberg (DKFZ), July 1st 2021

  • Laboratory Animal Science Course (EU Function A, FELASA) - Theoretical and Practical course, Frankurt

  • Morphological and mitochondrial changes in murine choroid plexus epithelial cells during healthy aging, Valentina Scarpetta. IZN seminar talk, 14.06.2023

  • Data report PhD Students 37th cycle (Dott. Garcia Bejarano Marina's PhD Student Discussant). 15th February 2023, Turin.

National meeting of PhD Students in Neuroscience. 14th September 2023, Turin, Italy

20th National Congress of the Italian Society for Neuroscience (SINS). 14-17 September 2023, Torino, Italy

FENS Regional meeting. 3-5 May 2023, Algarve, Portugal.

FENS Forum 2022. 9-13, July 2022, Paris, France.

National meeting of PhD Students in Neuroscience. 11th June 2022, Brescia, Italy

MOTOR NEURON DISEASES, Understanding the pathogenic mechanisms to develop therapies - Virtual Conference, 7th-8th November 2020

 

Scarpetta V, Bodaleo F, Salio C, Agarwal A, Sassoè M, Patrizi A. MORPHOLOGICAL AND MITOCHONDRIAL CHANGES IN MURINE CHOROID PLEXUS EPITHELIAL CELLS DURING HEALTHY AGING. - DKFZ PhD Poster presentation. 9 November 2023, Heidelberg, Germany.

Scarpetta V, Bodaleo F, Salio C, Agarwal A, Sassoè M, Patrizi A. MORPHOLOGICAL AND MITOCHONDRIAL CHANGES IN MURINE CHOROID PLEXUS EPITHELIAL CELLS DURING HEALTHY AGING. - 20th National Congress of the Italian Society for Neuroscience (SINS). 14-17 September 2023, Torino, Italy.

Scarpetta V, Bodaleo F, Salio C, Agarwal A, Sassoè M, Patrizi A. MORPHOLOGICAL AND MITOCHONDRIAL CHANGES IN MURINE CHOROID PLEXUS EPITHELIAL CELLS DURING HEALTHY AGING. - National meeting of PhD Students in Neuroscience. 14th September 2023, Torino, Italy.

Scarpetta V, Bodaleo F, Salio C, Agarwal A, Sassoè M, Patrizi A. MORPHOLOGICAL AND MITOCHONDRIAL CHANGES IN MURINE CHOROID PLEXUS EPITHELIAL CELLS DURING HEALTHY AGING. FENS Regional meeting. 3-5 May 2023, Algarve, Portugal.

Ho K, Scarpetta V, Salio C, D’Este E, Meschkat M, Wurm C, Sassoè M, Patrizi A. THE ATYPICAL CILIA OF CHOROID PLEXUS THROUGH DEVELOPMENTAL LENSES. EMBO Cilia2022, 5th European cilia conference. 4-7 October 2022, Cologne, Germany.

Scarpetta V, Bodaleo F, Salio C, Sassoè M, Agarwal A, Patrizi A. MORPHO-FUNCTIONAL ALTERATIONS IN EPITHELIAL CELLS OF THE CHOROID PLEXUS DURING AGING. - FENS Forum 2022. 9-13, July 2022, Paris, France.

Ho K, Scarpetta V, Salio C, D’Este E, Sassoè M, Patrizi A. THE ATYPICAL CILIA OF CHOROID PLEXUS THROUGH DEVELOPMENTAL LENSES. FENS Forum 2022. 9-13, July 2022, Paris, France.

Scarpetta V, Bodaleo F, Salio C, Sassoè M, Agarwal A, Patrizi A. MORPHO-FUNCTIONAL ALTERATIONS IN EPITHELIAL CELLS OF THE CHOROID PLEXUS DURING AGING. -National meeting of PhD Students in Neuroscience. 11th June 2022, Brescia, Italy.

Scarpetta V, Signorino E, Vercelli A, Boido M. CHARACTERIZATION OF PERIPHERAL ALTERATIONS IN A MURINE MODEL OF SPINAL MUSCULAR ATROPHY: A FOCUS ON SKELETAL MUSCLES AND SPLEEN. - MOTOR NEURON DISEASES, Undestanding the pathogenic mechanisms to develop therapies. Virtual Conference, 7th-8th November 2020.

 

Scarpetta, V.; Bodaleo, F.; Salio, C.; Agarwal, A.; Sassoè, M.; Patrizi, A. Morphological and mitochondrial changes in murine choroid plexus epithelial cells during healthy aging. Fluids Barriers CNS20, 19 (2023). https://doi.org/10.1186/s12987-023-00420-9

Ho K.; Scarpetta V.; Salio C.; D’Este E.; Meschkat M.; Wurm C.; Kneussel M.; Janke C.; Magiera M.; Sassoè M.; Brill M.; Patrizi A. Intrinsic microtubule destabilization of multiciliated choroid plexus epithelial cells during postnatal lifetime. BioRxiv preprint doi: https://doi.org/10.1101/2023.01.10.523428

Ho K.; Candat A.; Scarpetta V.;  Faucourt M.; Weill S.; Salio C.; D’Este E.; Meschkat M.; Wurm C.; Kneussel M.; Janke C.; Magiera M.; Genovesio A.; Meunier A.; Sassoè M.; Brill M.; Spassky N.; Patrizi A. Choroid plexus carry nodal-like cilia that undergo axoneme regression from early adult stage. Developmental cell, October 26 (2023). doi: https://doi.org/10.1016/j.devcel.2023.10.003

 

 

Premio Enrica Marzola 2023 with the scientific paper "Morphological and mitochondrial changes in murine choroid plexus epithelial cells during healthy aging".

Best poster award. Morphological and mitochondrial changes in murine choroid plexus epithelial cells during healthy aging. - 20th National Congress of the Italian Society for Neuroscience (SINS 2023). 14-17 September 2023, Torino, Italy

Best poster award. MORPHO-FUNCTIONAL ALTERATIONS IN EPITHELIAL CELLS OF THE CHOROID PLEXUS DURING AGING. - National meeting of PhD Students in Neuroscience. 11th June 2022, Brescia, Italy.

Thanks to an ongoing collaboration with Dr. Annarita Patrizi at the German Cancer Research Center (DKFZ), a laboratory focused on understanding the role of the ChP during brain development and function in normal and pathological states, I have the possibility to spend several months in Heidelberg and in particular at the DKFZ, one of the most renowned research centers in Germany, and to both take advantage of the expertise of Patrizi’s group in working with such complex tissue and learning multiple techniques, but also to benefit from a stimulating environment that offered me the possibility of joining the DKFZ PhD educational program and all its courses/workshops. 

Visiting PhD student at the German Cancer Research Center (DKFZ) in the 'Neuronal Signaling and Morphogenesis' laboratory, under the supervision of Dr. Annarita Patrizi.

  • 8.11.2020 - 31.05.2021
  • 28.12.2021 - 10.06.2022
  • 8.07.2022 - 4.11.2022
  • 20.04.2023 - 24.05.2023
  • 3.06.2023 - 7.07.2023
  • 20.07.2023 - 22.12.2023

Publications

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Last update: 08/01/2024 15:19
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