Neurodegenerative disorders are complex pathological conditions that involve, among other processes, synaptic loss and neuronal cell death leading to deterioration of neuronal structure and function. Neurodegenerative diseases are the second leading cause of death and a major cause of disability. The development of strategies to cure or at least delay the progression of neurodegenerative diseases has been hindered by their diverse etiology and complex nature, and by the limited regenerative capacity of neurons. There is thus an urgent need for effective medical interventions. As part of the central nervous system (CNS), the retina shares multiple pathophysiological features with the brain, and retinal neurodegenerative diseases, like those affecting the brain, are characterized by synaptic failure and neuronal cell death. Retinitis Pigmentosa (RP) refers to a group of inherited retinal dystrophies that are clinically similar despite arising from of a large set of genetic mutations; more than 60 genes and 3,000 mutations have been identified up to date ( RP is the most common cause of inherited blindness in people between 20 and 60 years old. It its categorized as a rare disease (prevalence 1/3,500-4,000) and affects around 2 million people. Most if not all forms of RP share molecular and cellular mechanisms that include inflammation, macro and microglial activation and photoreceptor cell loss. RP is an unpreventable and incurable rare disease that leads to blindness. Gene therapy would be the ideal definitive treatment, however, the genetic complexity in the etiology of RP calls for the development of treatments targeting common pathological mechanisms independently of the causative mutation.

Retinal section of a mouse model of Retinitis Pigmentosa. Nuclei are stained in blue. GFAP labeling (cyan) of Muller glia cell and astrocyte gliosis.
Retinal section of a mouse model of Retinitis Pigmentosa. Nuclei are stained in blue. GFAP labeling (cyan) of Muller glia cell and astrocyte gliosis.

Neuroinflammatory processes constitute a common burden to brain and retinal disorders, however, attempts to interfere in animal models with some aspects of the inflammatory response, have rendered sometimes conflicted results. This highlights the need of increasing the knowledge of the pathological mechanisms of the disease before considering novel therapeutic approaches. In our group we tackle three key elements of the inflammatory process associated not only to retinal dystrophies but also to other neurodegenerative diseases: i) innate immune response receptors, including the Toll-like receptors (TLR). TLR activation, either by Pathogen-Associated Molecular Patterns (PAMP) or by Damage-Associated Molecular Patterns (DAMP), generates an inflammatory response. TLR activation seems to display dual effects, either protection or exacerbation of neurodegenerative pathologies. ii) alarmines, like the High Mobility Group Box 1 (HMGB1) that may act as a damage signal. HMGB1 is a nuclear chaperone that upon cellular damage can be released extracellularly, where it activates innate immune response receptors like TLR. iii) the complement system, another player of the innate immune response which has been involved in neurodegenerative processes. To this aim, we employ two genetically unrelated models of RP, the rd10 and the P23H mice, to sustain our observations as mutation-independent processes. In all the case, we pursue whether the modulation of those processes identified as relevant may constitute a potential therapy.

In addition, we have assayed neuroprotective strategies based in our previous neurodevelopmental studies. Since the insulin precursor proinsulin (Pi) promoted neuronal differentiation and downregulated developmental cell death we have started exploring its possible therapeutical application in neurodegenerative diseases. Proinsulin delays photoreceptor cell death in several models of RP in mice and rats, prolonging their visual function. Moreover, proinsulin attenuated the age-associated cognitive impairment. 

Mouse retinal bipolar cells stained in green and their synaptic terminals in red
Mouse retinal bipolar cells stained in green and their synaptic terminals in red

Our global line of research aimed to advance the knowledge of the cellular y molecular alterations associated to RP and by extension to neurodegenerative process, as well as to identify novel pharmacological targets and to perform initial proofs of concept for potential RP therapies.

 •    Sánchez-Cruz A, Villarejo-Zori B, Marchena M, Zaldivar-Díez J, Palomo V, Gil C, Lizasoain I , de la Villa P, Martínez A, de la Rosa EJ and Hernández-Sánchez C. [2018]. Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa. Mol Neurodegener Apr 16;13(1):19. DOI: 10.1186/s13024-018-0251-y.


•    Platón-Corchado M, Barcelona PF, Jmaeff S, Marchena M, Hernández-Pinto AM, Hernández-Sánchez C, Saragovi HU, de la Rosa EJ. [2017]. p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa. Cell Death Dis. 2017 Jul 13;8(7):e2922. DOI: 10.1038/cddis.2017.306.

  • Corpas R, Hernández-Pinto AM, Porquet D, Hernández-Sánchez C, Bosch F, Ortega-Aznar A, Comellas F, de la Rosa EJ, Sanfeliu C. [2017]. Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways. Neuropharmacology. 2017 Sep 1;123:221-232. DOI: 10.1016/j.neuropharm.2017.06.014. 
  • Isiegas C, Marinich-Madzarevich JA, Marchena M, Ruíz JM, Cano MJ, de la Villa P, Hernández-Sánchez C, de la Rosa EJ, De Pablo F. [2016].  Intravitreal injection of proinsulin-loaded microspheres delays photoreceptor cell death and vision loss in the rd10 mouse model of retinitis pigmentosa. Invest. Ophtalmol. Vis. Sci. 57, 3610-18

Participants: Alonso Sánchez, Noemí Álvarez Lindo, Cayetana Murillo, Mateo Pazo González and Noelia Pimentel Mayordomo.

Colaborators: Pedro de la Villa (Universidad de Alcalá), Fátima Bosch (Universidad Autónoma de Barcelona), Nicolás Cuenca (Universidad de Alicante), Regina Rodrigo (Hospital La Fe), Ana Martínez (CIB), Ignacio Lizasoain (Universidad Complutense), Uri Saragovi (McGill University) and Patricia Becerra (NEI-NIH). 

Heads:  Enrique J de la Rosa and Catalina Hernández-Sánchez


Laboratorio 3D: Desarrollo, Diferenciación y Degeneración