Sheddome and Disease Lab

 

 

Overview of research

Our research focuses on understanding how the process of ectodomain shedding regulates neuronal (dys)function. Ectodomain shedding consists of a protease cleaving the extracellular domain of proteins attached to the cell membrane, resulting in the release of a soluble extracellular fragment.

Figure 1: Illustration of ectodomain shedding.

The cleaved ectodomains possess biological activity, acting as signaling molecules to regulate the function of nearby and distant neurons. Thus, it is not surprising that dysregulation of ectodomain shedding has been linked to several human disorders. In the Sheddome & Disease Lab, we aim to understand how ectodomain shedding contributes to autism, schizophrenia, and epilepsy. To achieve our goal, we employ both in vitro and in vivo models to dissect cellular and molecular changes regulated by ectodomain shedding. We use a wide array of techniques including advanced biochemistry, molecular biology and imaging techniques, together with proteomics and bioinformatics.

Finding new mechanisms associated with brain conditions is vital for improving treatment strategies, finding new diagnostic tools, and ultimately enhancing the overall well-being of individuals affected by them.

In the Sheddome and Disease Lab, we investigate the molecular and cellular mechanisms that are altered in neuropsychiatric conditions, with a particular emphasis on neurodevelopmental conditions such as autism, epilepsy, or schizophrenia. Our final goal is to find new biomarkers and therapies for them.

Our current research objectives are:

• Investigating the role of ectodomain shedding in autism and other neuropsychiatric conditions.
• Studying the neuronal functions of risk molecules for neuropsychiatric disorders, particularly those that are regulated by ectodomain shedding.
• Understanding how protein regulation by ectodomain shedding impacts synapses and neuronal communication.

 

Figure 2: CNTNAP2 ectodomain stained in cortical neurons

Lab members

Group leader

Dolores Martín de Saavedra, PhD. Ramón y Cajal Researcher

 

Students

• Miguel Lobete. PhD student, FPI Contract 2023-2027
• Marta Cámara. Undergraduate student 2024/25
• Sara Polo. Master's student 2024/25
• Silvia Socas. Master’s student 2023/24
• Tamel Salinas. Master’s student 2022/23

 

Selected publications

• Lobete M, Dionisio LE, McCoig E, Piguel NH, Spielman BP, Socas S, dos Santos M, Boers-Escuder C, Penzes P, Martin-de-Saavedra MD. 2024. ASD-Associated CNTNAP2 Variants Disrupt Neuronal Arborization Through Impaired Regulation by Ectodomain Shedding. bioRxiv [Preprint]. DOI: 1101/2024.11.04.621898v1
• Lobete M, Salinas T, Izquierdo-Bermejo S, Socas S, Oset-Gasque MJ, Martin-de-Saavedra MD. 2024. A methodology to globally assess ectodomain shedding using soluble fractions from the mouse brain. Frontiers in Psychiatry. DOI: 3389/fpsyt.2024.1367526
• Martín-de-Saavedra MD; Santos MD.; Culotta L.; et al; Penzes P. 2022. Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2. Neuron. 627-643. DOI: 10.1016/j.neuron.2021.11.025
• Martín-de-Saavedra MD; Santos MD; Penzes P. 2022. Intercellular signaling by ectodomain shedding at the synapse. Trends in Neurosciences. pp.483-498. 1016/j.tins.2022.03.004
• Zaccard CR.; Shapiro L; Martin-de-Saavedra MD; et al; Penzes P. 2020. Rapid 3D Enhanced Resolution Microscopy Reveals Diversity in Dendritic Spinule Dynamics, Regulation, and Function. 107-3. DOI: 10.1016/j.neuron.2020.04.025
• Gao, R; Piguel NH*; Melendez-Zaidi AE*; Martín-de-Saavedra MD; …; Penzes, P. 2018. CNTNAP2 stabilizes interneuron dendritic arbors through CASK. Molecular Psychiatry. 23 – 9. DOI: 1038/s41380-018-0027-3
• Martin-de-Saavedra MD; Navarro E; Moreno-Ortega AJ.; et al; Lopez MG. 2018. The APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation, Ca2+ dysregulation, and mitochondrial abnormalities. Journal of Neurochemistry. 170-182. DOI: 10.1111/jnc.14293
• Blizinsky KD; Diaz-Castro B; Forrest MP; …; and Penzes P. Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub. 2016. PNAS. 113 - 30, pp. 8520 - 8525. 1073/pnas.1607014113
• Varea O; Martin-de-Saavedra MD; Kopeikina KJ et al; Penzes P. 2015. Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons. pp.6176-6181. DOI: 10.1073/pnas.1423205112

 

Funding

Contribution of protein ectodomain shedding to autism spectrum disorders. “Agencia Estatal de Investigación”. PI: Martin de Saavedra MD (Universidad Complutense de Madrid). Awarded with an FPI predoctoral training contract. 2022-2025.

 

Contact information

School of Pharmacy, Universidad Complutense de Madrid

Department of Biochemistry and Molecular Biology, Lab 13

Plaza Ramón y Cajal s/n

28040 Madrid (Spain)

Phone: (+34) 91 394 1854

e-mail: dolores.ms@ucm.es

Visit here the Sheddome and Disease Lab web page