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Visualisation of neuronal polysomal architecture and its alterations in Huntington's Disease

18th national competition for scientific and technical research

Rare diseases

Senior Researcher : José Jesús Fernández Rodríguez

Research Centre or Institution : Centro Nacional de Biotecnología (CNB). CSIC. Madrid


Huntington’s disease (HD) is an inherited disorder that initially involves the selective degeneration of the striatal medium-sized spiny neurons (MSSN) and, at later stages, of cerebral cortex neurons. The disease is clinically characterized by motor, cognitive and psychiatric manifestations. Despite the extensive research since the discovery of its genetic cause, the precise pathophysiological mechanisms of HD are poorly understood and there is still no effective treatment for the disease. Our working hypothesis is that the maintenance of subcellular architecture is of paramount importance for neuronal homeostasis. Identification of alterations associated to neurodegeneration may thus contribute to gain insights into the pathophysiological basis of different diseases and enable the identification of new targets for therapeutic intervention.

In this project we are studying the architecture of the protein synthesis machinery, which plays an essential role in neuronal homeostasis. Our aim is the identification and characterization of polysomal alterations in HD and the exploration of the therapeutic potential of molecules that may reverse them. As central tools, we use electron tomography and advanced methods of three-dimensional (3D) image processing, in combination with protocols for optimal structural preservation of brain tissue.

These years we have conducted an in situ 3D analysis of the neuronal polysomal organization using state-of-the-art electron microscopes and developing innovative image-processing methods. The analysis of the 3D volumes have enabled the quantitative assessment based on methods for automated identification of ribosomes and the study of their clustering/dispersion by means of spatial analysis techniques. This strategy has confirmed that there exist specific alterations in the striatal medium-sized spiny neurons in the HD murine model Q175 that consist in ribosomal clustering.

To gain insights into the molecular mechanism underlying these structural alterations and analyse their relevance in the pathophysiology of HD, we have obtained polysomal sedimentation profiles. They have confirmed that the ribosomal organization is altered, showing an imbalance of the ribosomal subunits and the activation of proteins associated to the rescue of stalled ribosomes in the HD murine model.


Scientific Production
Magazine Articles 5
Communications at national conferences 2
Communications at international conferences 4


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