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Molecular Medicine Programme | Neurosciences

Molecular Pathology of Rare Diseases

Jesús R. Requena
Leader Prion lab | Associate Professor
jesus.requena@usc.es
 
Prion Lab: PSSL6
UETeM Lab: P2L3
Field of knowledge

The Molecular Pathology of Rare Diseases Group is divided into two sections:

  1. The Prion lab, led by Jesús Requena.
  2. The Lipodystrophy Unit lab, led by David Araujo-Vilar.

Prion Lab:

Our research focus is the biochemistry of prions and prion-like misfolded proteins. Prions are infectious proteins. PrPSc prions cause lethal neurodegenerative diseases, the transmissible spongiform encephalopathies. They became notorious during the European mad cow disease crisis. We aim, on the one hand, at understanding the molecular underpinnings of  the propagation of PrPSc prions. On the other, at identifying a therapeutic strategy for these incurable diseases. But PrPSc prions are not the only misfolded proteins that cause neurodegenerative diseases: misfolded Aβ, tau and -synuclein are involved in devastating and widespread ailments such as Alzheimer´s disease (AD) and there is very solid experimental support of the notion that their prion-like propagation within the brain is key to their pathogenicity. We aim at identifying the underpinnings of their toxicity.

 

Lipodystrophy Unit (UETeM):

  • Unfrequent lipodystrophy syndromes
  • Ageing and progeroid syndromes
  • Rare severe insulin resistance syndromes
  • Adipose tissue and molecular mechanisms of adipogenesis
  • Neurodegeration and rare neurodegenerative disorders 
  • Diagnostic approach of lipodystrophy syndromes through Artificial Inteligence
  • Rare diseases registries 
  • Novel treatments for lipodystrophy syndromes 

Research Lines

Prion Lab:

  • Understanding the propagation of PrPSc prions.  PrPSc is the first prion to be identified and is the quintessential prion. It causes fatal neurodegenerative ailments such as Creutzfeldt-Jakob disease of humans, scrapie of sheep, bovine spongiphorm encephalopathy (mad cow disease) or chronic wasting disease (zombie deer disease) of cervids. PrPSc is a misfolded conformer of a brain protein termed PrPC.  We aim at understanding how PrPSc propagates. In 2016 we published, in collaboration with colleagues, the first cryoelectron microscopy (cryoEM) study of PrPSc ever. And in 2018, in collaboration with Italian colleagues, the first atomic-level modelization of PrPSc propagation. PrPSc is an amyloid, and PrPC has a C-terminal globular domain featuring and an intrinsically disordered N-terminal domain. We believe that conversion is initiated by attachment of the disordered N-terminal domain to the surface of the PrPSc amyloid. The NH- and CO- groups of the β-strands that make up such surface, are avid to trap and template an incoming disordered PrP stretch. Then, the globular C-terminal domain of that incoming PrPC conformer must unfold partially so it can be templated/refolded from coil to β-strand secondary structure. We are using protein NMR, cryoEM and biochemical techniques to refine our 2018 conversion model.
  • Identifying a therapy for prion diseases. Prion diseases are fatal and all attempts to identify a therapy have failed to date. Among these, some of our own. However, these failures have not deterred the many groups that continue to pursue such objective, including ourselves. The recent modest, proof of principle success of the monoclonal antibody Lecanemab for the treatment of AD is an inspiration to persevere.  Currently we are conducting a study based on the use of a fungal prion that is non-infectious to mammals as a vaccine. Our rationale is that the linear amino acid repeats along every amyloid might act as generic antigens.

    We are also participating in an experiment that will be carried out at the International Space Station (launch May 6, 2023) in which we aim at characterizing the interaction of a PrPC folding intermediate and a potential drug targeting it that has been identified in silice. This is a proof of concept experiment and we aim at further pursuing this line of space research.

  • Targeting of early amyloid seeds at the initial stage of neurodegenerative diseases. In AD, the amyloid cascade hypothesis posits that the pathogenesis is initially caused by the cerebral deposition of Aβ while in Parkinson’s disease (PD), the pathological aggregation of alpha-synuclein (α-syn) as Lewy bodies in neurons is the key pathological event. Both Aβ and α-syn deposition follow a prion-like mechanism, in which pathogenic amyloid aggregates (seeds), formed early in the aggregation pathway, induce the misfolding and aggregation of proteins in the brain.

    Our hypothesis is that early seeds are different in structure and/or composition than other aggregated amyloid forms (such as fibrils or protofibrils). These unique features make them the ideal target for potential therapeutic agents targeting the initial stage of AD and PD and a promising early biomarker for these diseases.

    We aim to isolate and purify early seeds, biochemically and structurally characterize them, and find therapeutic compounds capable to block their seeding capacity. In parallel, we pursue the development of antibodies against such early seeds with both therapeutic and detection potential.
     

Lipodystrophy Unit (UETeM):

  • Murine model of Celia's encephalopathy
  • Murine model of type 2 Congenital Genealized Lipodystrophy
  • Biometry, BigData and Artificial Inteligence for clinical diagnose of rare lipodystrophy syndromes
  • Changes of epigenetic marks in adipose tissue in the pathogenesis of lipodystrophy syndromes
  • Pathogenic mechanisms of acanthosis nigricans in severe insulin resistance syndromes
  • European registry of lipodystrophies
  • Molecular mechanisms of lipomatosis in laminopathic and mitochondrial disorders
  • New drugs for treating lipodystrophy co-morbidities

Members

David Araujo-Vilar
Professor of Medicine
david.araujo@usc.es
Alejandro Iván Ruíz Riquelme
María Zambrano Grant Investigator
alejandroivan.ruiz@usc.es
Álvaro Hermida Ameijeiras
Associate professor
alvaro.hermida@usc.es
Antía Fernandez-Pombo
Post-doctoral investigator
antiafpombo@gmail.com
Sofía Sánchez Iglesias
Assistant professor
sofia.sanchez@usc.es

 

Sonia Veiga Sans
Research Specialist Technician
Sanaz Sabzehei
PhD student
Raúl Cacheiro Vázquez
Xunta de Galicia fellowship
Nuria López Lorenzo
PhD student
Silvia Cobelo Gómez
PhD student
Ekaterina Makarova
PhD student
Everardo José Díaz López
PhD student
Teresa Prado Moraña
PhD student

Selected publications

Full atomistic model of prion structure and conversion

Spagnolli, G; Rigoli, M; Orioli, S; Sevillano, AM; Faccioli, P; Wille, H; Biasini, E; Requena, JR
Recombinant PrPSc shares structural features with brain-derived PrPSc : Insights from limited proteolysis
Sevillano, Alejandro M.; Fernandez-Borges, Natalia; Younas, Neelam; Wang, Fei; Elezgarai, Saioa R.; Bravo, Susana; Vazquez-Fernandez, Ester; Rosa, Isaac; Erana, Hasier; Gil, David; Veiga, Sonia; Vidal, Enric; Erickson-Beltran, Melissa L.; Guitian, Esteban; Silva, Christopher J.; Nonno, Romolo; Ma, Jiyan; Castilla, Joaquin; Requena, Jesus R.
The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy.
Vázquez-Fernández E, Vos MR, Afanasyev P, Cebey L, Sevillano AM, Vidal E, Rosa I, Renault L, Ramos A, Peters PJ, Fernández JJ, van Heel M, Young HS, Requena JR, Wille H.
The Structure of PrPSc Prions
Wille, Holger; Requena, Jesus R.

Clinical Spectrum of LMNA-Associated Type 2 Familial Partial Lipodystrophy: A Systematic Review.

Fernandez-Pombo A, Diaz-Lopez EJ, Castro AI, Sanchez-Iglesias S, Cobelo-Gomez S, Prado-Moraña T, Araujo-Vilar D.

Lipodystrophy-associated progeroid syndromes.

Araújo-Vilar D, Fernández-Pombo A, Cobelo-Gómez S, Castro AI, Sánchez-Iglesias S.

Characterization and Clinical Association of Autoantibodies Against Perilipin 1 in Patients With Acquired Generalized Lipodystrophy.

Corvillo F, Abel BS, López-Lera A, Ceccarini G, Magno S, Santini F, Araújo-Vilar D, Brown RJ, Nozal P, López-Trascasa M

Complement Factor D (adipsin) Levels Are Elevated in Acquired Partial Lipodystrophy (Barraquer-Simons syndrome)

Corvillo F, González-Sánchez L, López-Lera A, Arjona E, Ceccarini G, Santini F, Araújo-Vilar D, Brown RJ, Villarroya J, Villarroya F, Rodríguez de Córdoba S, Caballero T, Nozal P, López-Trascasa M

Selected Results

Projects

National project(s)

Personalized medicine for rare diseases: diagnosis by biometrics and artificial intelligence and modifications in epigenetic marks in rare lipodystrophies.
REF: PI22/00514Duration: -
PI: David Araújo-Vilar
INSTITUTO DE SALUD CARLOS III
Revelando compuestos con capacidad de bloquear semillas amiloides tempranas en enfermedad de Alzheimer.
REF: PID2021-126584OA-100Duration: -
PI: Alejandro Ivan Ruiz Riquelme
AGENCIA ESTATAL DE INVESTIGACION
Elucidación de la estructura de los priones PrPSc recombinantes basada en RMN de estado sólido -GENERACIÓN DE CONOCIMIENTO 2020
REF: PID2020-117465GB-I00Duration: -
PI: Jesús Rodríguez Requena
AGENCIA ESTATAL DE INVESTIGACION

Patents

Transgenic non-human models for lipodystrophy and/or PELD
Aplication Nº: EP19382828
Lipo-DDx
Aplication Nº: 03/2019/1209
Stellum-MMg
Aplication Nº: 1996-15-21271
Methods to differentiate protein conformers.
Aplication Nº: US 8445642
Bruce C. Onisko, Christopher J. Silva, Jesus R. Requena, John Mark Carter.