Desenvolupament d'estratègies terapèutiques per l'esclerosi lateral amiotròfica

• Autores: Maria Puigdomenech Poch
• Directores de la Tesis: Rubén López Valés (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
• Idioma: español
• ISBN: 9788449096716
• Tribunal Calificador de la Tesis: Silvia Ginés Padros (presid.), Assumpció Bosc Merino (secret.), Esther Pérez Navarro (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Autónoma de Barcelona
• Materias:
  • Ciencias médicas
    • Patología
      • Neuropatología
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder with no effective treatment currently available. ALS is characterized by the progressive loss of both upper and lower motoneuron (MN) and the consequent muscle atrophy. Nowadays the specific molecular mechanism that underline the MN death is unknown, however has been related several dysfunction mechanisms in MNs and the surrounding cells, such: oxidative stress, inflammation or aggregation of aberrant proteins like superoxide dismutase 1 (SOD1). In this thesis we propose two therapeutic strategies for ALS: increase the silencing efficiency of the mutated SOD1, by means of gene therapy and study the role of the lysophosphatidic acid (LPA) in the pathophysiology of ALS.

    In the first chapter, with the aim to reduce the RNA levels of the SOD1 mutated, we administrated antisense oligonucleotide (ASO) conjugated to specific ligands to increase the internalization of the molecule. The results present here reveal the efficient internalization of the therapy in neurons and glia cells. Furthermore, the conjugated- ASO with the ligand DCPP reduce more efficiently than the unconjugated ASO, the SOD1 RNA levels in the SOD1G93A mice, an experimental model of ALS. However, the administration of the conjugated-ASO with the ligand DCPP in the SOD1G93A mice, does not present therapeutic effects.

    In the second chapter, since inflammation is a hallmark of most neurological conditions and LPA2 has been reported that contribute to the pathophysiology of spinal cord injury, we wonder if LPA could be involved in the pathophysiology of ALS. To assess whether activation of LPA2 contributes to ALS, we crossed LPA2 null with SOD1G93A mice. Our results reveal that the absence of LPA2 delays onset and progression of the disease and prevent the muscle atrophy in ALS mice.

    Collectively the results presented here provide more novel data that could underline new therapeutic strategies for ALS.