Research Group on Neurobiology and Molecular Physiopathology in Rare Diseases – NeuroFisER

Metabolism and Organic Damage Area


Rare diseases, also known as minority or orphan diseases, are a group of pathologies with a great heterogeneity. They affect a small number of individuals, which are, in most cases, disabling and even fatal, suffering from an important lack of resources for their treatment.
Our main field of study are neuromuscular diseases, and especially ataxias. Our principal objective is to determine the molecular mechanisms underlying these diseases. Thus, our group we is mainly interested in two types of ataxias: Friedreich’s ataxia (FRDA) and CANVAS Syndrome (Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome).

FRDA is the most frequent clinical form of hereditary ataxias. Understanding the pathophysiology of the disease at the molecular level allows us to identify new therapeutic targets to implement more effective treatments than the current ones for Friedreich’s ataxia. To this end, we study the pathophysiology of the disease using different models. In addition, we are focused on developing new advanced gene therapy strategies using the CRISPR/Cas9 system.

The most recent line of research treats with CANVAS syndrome, a recently diagnosed disabling neurological disease. Our study comprises the generation of iPSCs from skin biopsies of CANVAS patients, and their subsequent differentiation to sensory neurons to obtain a working model. The characterization of the neurons obtained, together with the genetic and clinical screening carried out by our collaborators, will allow us to better understand the pathophysiology of this disease.

Finally, we are developing a line of research focused on Huntington’s disease, where we generate a series of tools to reduce the levels of mutant huntingtin as a therapeutic approach to modify the progress of the disease. Specifically, we are using nanobodies, which are the single-chain variable region of camelid antibodies, fused to ubiquitin ligase domains. This proof of concept consists of obtaining the nanobodies as therapeutic molecules with the capacity to target the mutant huntingtin towards the proteasome for its degradation.

Coordinator
Dra. Pilar González Cabo
pilargc@uv.es
RESEARCHERS
Leading, R4
Established, R3

Pilar González Cabo    

Recognised/Emerging, R2

Noelia Benetó Gandía

First Stage, R1

Laura Robles Rodríguez

STAFF
Collaborating Researchers
Nurse
Technicians
Administrative assistant
Publications

Cofilin and neurodegeneration: new functions for an old but gold protein. Lapena-Luzon T, Rodriguez L, Beltran-Beltran V, Beneto N, Pallardo F, Gonzalez-Cabo P. Brain Sciences. 2021 Jul 20;11(7):954. doi: 10.3390/brainsci11070954. PMID: 34356188Friedreich Ataxia: current state-of-the-art, and future prospects for mitochondrial-focused therapies. Pallardo Calatayud F, Pagano G, Rodriguez Melguizo L, González Cabo P, Lyakhovich A, Trifuoggi M. Translational Research. 2021 Mar;229:135-141. doi: 10.1016/j.trsl.2020.08.009. PMID: 32841735

Role of adenosine receptors in rare neurodegenerative diseases with motor symptoms. Beltran-Beltran V, Beneto N, Lapena-Luzon T, Rodriguez LR, Pallardo FV, Gonzalez-Cabo P. Current Protein & Peptide Science. 2021 Dec 27;22(9):675-694. doi: 10.2174/1389203722666210910110126. PMID: 34514988

Antioxidant Therapies and Oxidative Stress in Friedreichs Ataxia: The Right Path or Just a Diversion?. Rodriguez Melguizo L, Lapeña Luzón T, Calap Quintana P, Moltó Ruiz M, González Cabo P, Navarro Langa J. Antioxidants (Basel, Switzerland). 2020 Jul 24;9(8):664. doi: 10.3390/antiox9080664. PMID: 32722309Cofilin dysregulation alters actin turnover in frataxin-deficient neurons. Muñoz Lasso D, Molla B, Calap Quintana P, Garcia Gimenez J, Pallardo Calatayud F, Palau F, González Cabo P. Scientific Reports. 2020 Mar 23;10(1):5207. doi: 10.1038/s41598-020-62050-7. PMID: 32251310

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders. Muñoz Lasso D, Roma Mateo C, Pallardo Calatayud F, González Cabo P. Cells. 2020 Feb 4;9(2):358. doi: 10.3390/cells9020358. PMID: 32033020

Oxidative stress modulates rearrangement of endoplasmic reticulum-mitochondria contacts and calcium dysregulation in a Friedreich’s ataxia model. Rodríguez LR, Calap-Quintana P, Lapeña-Luzón T, Pallardó FV, Schneuwly S, Navarro JA, Gonzalez-Cabo P. Redox Biology. 2020 Oct 16;37:101762. doi: 10.1016/j.redox.2020.101762. PMID: 33128998

PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia. Rodriguez-Pascau L, Britti E, Calap Quintana P, Dong Y, Vergara C, Delaspre F, Medina M, Tamarit J, Pallardo Calatayud F, González Cabo P, Ros J, Lynch D, Martinell M, Pizcueta P. Neurobiology of Disease. 2020 Nov 7;148:105162. doi: 10.1016/j.nbd.2020.105162. PMID: 33171227

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia. Seco-Cervera M, Gonzalez-Cabo P, Pallardo F, Roma-Mateo C, Garcia-Gimenez J. Antioxidants. 2020 Dec 10;9(12):E1257. doi: 10.3390/antiox9121257. PMID: 33321938

Projects
Referencia: ACCI 2020
Título: Síndrome de CANVAS: diagnóstico precoz y modelo fisiopatológico mediante iPSC.
Entidad Financiadora: Instituto de Salud Carlos III – Cofinanciado FEDER
Investigador principal: Pilar González Cabo
Duración: 2021 – 2022
Presupuesto: 75.000 €

Referencia: PID2020-115190RB-I00
Título: Relacionando cofilina, una proteína de unión a actina, con la desregulación del calcio: un enfoque de precisión para el tratamiento de la ataxia de Friedreich
Entidad Financiadora: Ministerio de Ciencia e Innovación
Investigador principal: Pilar González Cabo
Duración: 2021 – 2023
Presupuesto: 196.300 €

Referencia: ACCI-2019-22
Título: Degradación de la huntingtina mediante ubiquibodies de camélidos
Entidad Financiadora: CIBER de Enfermedades Raras (CIBERER-ISCIII)
Investigador principal: Pilar González Cabo
Duración: 2020 – 2022
Presupuesto: 18.000 €

Referencia: RTC2019-006825-1
Título: Potencial de la leriglitazona para el tratamiento de enfermedades asociadas a la acumulación de hierro, distrofias y enfermedades neuromusculares
Entidad Financiadora: Ministerio de Ciencia e Innovación
Investigador principal: Pilar González Cabo
Duración: 2020 – 2023
Presupuesto: 90.000 €

Referencia: ACCI-CIBERER 2018
Título: Edición Génica del Gen FXN mediante el Sistema CRISPR/Cas9 en linfocitos de pacientes con ataxia de Friedreich
Entidad Financiadora: CIBER de Enfermedades Raras (CIBERER-ISCIII)
Investigador principal: Pilar González Cabo
Duración: 2019 – 2021
Presupuesto: 39.750 €