Researcher
Sebastián Giusti.
Postdoc Students
Ivana Linenberg.
PhD Students
Camila Pannunzio,
Giuliana Di Mauro (co directed w/ Dr. Antonia Marin Burgin),
Maria Jose Santander (co directed w/ Dr. María Monge).
Undergraduate students
Lucía Szychowski,
Lautaro Bugner.
The neural circuits are constituted by a multiplicity of neurons that communicate through the release and action of neurotransmitters in interneuronal contacts called synapses. The human brain contains about 100 billion synapses. Far from being rigid structures, synapses are in constant structural and functional remodeling. These synaptic changes help explain, for instance, the processes of learning and memory. On the other hand, alterations in these processes of synaptic development, plasticity or remodeling can lead to different mental disorders, such as depression and anxiety, two psychiatric syndromes that our group have studied in detail.
Synapses are specialized junctions operated by highly complex protein-based molecular machineries whose composition and functional dynamics is tightly controlled by several post-translational modifications. Ubiquitin and Ubiquitin-like proteins (UBLs) like Sumo decisively control neuronal protein localization, interaction, turnover and activity, thereby regulating different aspects of dendritic and synaptic function. However, the role of other Ubiquitin-like proteins remains almost completely unknown.
Our group recently found that the UBL Nedd8, previously thought to exclusively influence cell proliferation, is the most highly expressed UBL in neurons and plays a fundamental role in synaptic development and stability. One of the main goals of the Molecular Neurobiology group is to elucidate the role of Nedd8 in neuronal development and function and its underlying molecular mechanisms, as well as its impact on cognitive and emotional behaviors.
Non-coding RNAs, including microRNAs, represent another central mechanism of post-transcriptional regulation of protein function and synthesis in dendritic and axonal microcompartments. Recently, our group has contributed to the identification and characterization of a new class of non-coding RNAs called circular RNAs (CircRNAs). These CircRNAs are highly expressed in the brain and enriched in synapses. However, its role in brain function and development in general and in synaptic activity in particular remains completely unexplored and is another aspect that our group tries to unravel.
Publications related to this project
- Giusti SA, Pino NS, Pannunzio C, Ogando MB, Armando NG, Garrett L, Zimprich A, Becker L, Gimeno ML, Lukin J, Merino FL, Pardi MB, Pedroncini O, Di Mauro GC, Durner VG, Fuchs H, de Angelis MH, Patop IL, Turck CW, Deussing JM, Vogt Weisenhorn DM, Jahn O, Kadener S, Hölter SM, Brose N, Giesert F, Wurst W, Marin-Burgin A, Refojo D.
A brain-enriched circular RNA controls excitatory neurotransmission and restricts sensitivity to aversive stimuli
Sci Adv. 2024 May 24;10(21):eadj8769. (2024) doi: 10.1126/sciadv.adj8769. - Fuchs Wightman F, Lukin J, Giusti SA, Soutschek M, Bragado L, Pozzi B, Pierelli ML, González P, Fededa JP, Schratt G, Fujiwara R, Wilusz JE, Refojo D*, de la Mata M*.
Influence of RNA circularity on Target RNA-Directed MicroRNA Degradation
Nucleic Acids Res. 12;52(6):3358-3374 (2024). doi: 10.1093/nar/gkae094.
*Corresponding authors - Muffels IJJ, Schene IF, Rehmann H, Massink MPG, van der Wal MM, Bauder C, Labeur M, Armando NG, Lequin MH, Houben ML, Giltay JC, Haitjema S, Huisman A, Vansenne F, Bluvstein J, Pappas J, Shailee LV, Zarate YA, Mokry M, van Haaften GW, Nieuwenhuis EES, Refojo D, van Wijk F, Fuchs SA, van Hasselt PM.
Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration
Am J Hum Genet 5;110(1):146-160 (2023). doi: 10.1016/j.ajhg.2022.12.003. - Szalai AM, Siarry B, Lukin J, Williamson DJ, Unsain N, Cáceres A, Pilo-Pais M, Acuna G, Refojo D, Owen DM, Simoncelli S, Stefani FD.
Three-dimensional total-internal reflection fluorescence nanoscopy with nanometric axial resolution by photometric localization of single molecules.
Nature Communications 12:517 (2021). - Vogl AM, Phu L, Becerra R, Giusti SA, Verschueren E, Hinkle TB, Bordenave MD, Adrian M, Heidersbach A, Yankilevich P, Stefani FD, Wurst W, Hoogenraad CC, Kirkpatrick DS, Refojo D*, Sheng M*.
Global site-specific neddylation profiling reveals that NEDDylated cofilin regulates actin dynamics.
Nat Struct Mol Biol 27:210-220 (2020).
*co-corresponding - Brockmann MM, Döngi M, Einsfelder U, Körber N, Refojo D, Stein V.
Neddylation regulates excitatory synaptic transmission and plasticity.
Sci Rep 9:17935 (2019) - Dedic N, Kühne C, Jakovcevski M, Hartmann J, Genewsky A, Gomes KS, Anderzhanova E, Pöhlmann M, Chang S, Kolarz A, Vogl AM, Metzger MW, Schmid B, Almada RC, Ressler KJ, Wotjak CT, Grinevich V, Chen A, Schmidt MV, Wurst W, Refojo D, Deussing JM.
CRH acts anxiolytic by modulating dopamine release through a subset of GABAergic long-range projection neurons.
Nat Neurosci 21:803-807 (2018) - Vogl AM, Brockmann MM, Giusti SA, Maccarrone G, Vercelli CA, Bauder CA, Richter JS, Roselli F, Hafner AS, Dedic N, Wotjak CT, Vogt-Weisenhorn DM, Choquet D, Turck CW, Stein V, Deussing JM, Refojo D.
Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition.
Nat Neurosci 18:239-51 (2015) - Rybak-Wolf A., Stottmeister C., Glazar P., Jens M., Pino N., Giusti S., Hanan M., Behm M., Bartok O., Ashwal-Fluss R., Herzog M., Schreyer L., Papavasileiou P., Ivanov A., Öhman M., Refojo D., Kadener S., Rajewsky N.
Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed.
Molecular Cell 58, 1–16 (2015) - Luxenhofer G, Helmbrecht MS, Langhoff J, Giusti S, Refojo D, Huber AB.
MicroRNA-9 promotes the switch from early-born to late-born motor neuron populations by regulating Onecut transcription factor expression.
Developmental Biology 386:358-70 (2014) - Giusti SA, Vogl AM, Brockmann MM, Vercelli CA, Rein ML, Trümbach D, Wurst W, Cazalla D, Stein V, Deussing JM, Refojo D.
MicroRNA-9 controls dendritic development by targeting REST.
Elife 3 (2014) - Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom C, Schütz G, Nave K-A, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM.
Glutamatergic and Dopaminergic Neurons Mediate Anxiogenic and Anxiolytic Effects of CRHR1.
Science 333:1903-1907 (2011)