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Cdk5: a therapeutic target for the treatment of motor and cognitive deficits in Huntington's disease

16th national competition for scientific and technical research

Rare diseases

Senior Researcher : Silvia Ginés Padrós

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Research Centre or Institution : Universidad de Barcelona.


Huntington's disease (HD) is a neurodegenerative disorder that mainly causes motor alterations due to the dysfunction and selective degeneration of the GABAergic neurons of the corpus striatum. Nevertheless, cognitive defects are observed in the initial phases of the disease and even years before the appearance of the classical motor symptoms. There is currently no treatment to prevent or cure the disease, or to stop it from progressing. The main aim of this project is to identify new therapeutic targets which may be able to treat the motor deficits as well as the cognitive disorders intrinsic to this disease. Cdk5 is a multifunctional kinase that may take part in a broad range of neuronal functions, from neuron growth to synaptic plasticity and cell survival. Increases in the activity of this kinase have been associated with the processes of neuron death characteristic of several neurodegenerative diseases, such as Alzheimer's or Parkinson's disease. In accordance with this pro-apoptotic role of Cdk5, the research group recently demonstrated that mutated huntingtin induces an overactivation of Cdk5 which in turn is responsible for the increased striatal susceptibility to glutamatergic and dopaminergic activation. Recent studies have also shown that Cdk5 activity is critical for learning processes and synaptic plasticity. Therefore, an aberrant activation of Cdk5 has been associated with cognitive deficits in different murine models. As a whole, these studies show Cdk5 to be a potential therapeutic target for the treatment of the motor and cognitive deficits in Huntington's disease. To this end, therapies aimed at inhibiting its activity may be beneficial for the treatment of this disease. Nevertheless, given the dual role of this kinase in the development and function of the nervous system as well as in neuronal death, the total inhibition of its activity may have harmful effects. It is therefore of crucial importance to define the molecular mechanisms by which mutated huntingtin induces the deregulation of its activity, as well as those Cdk5 targets which contribute to the pathology of the disease in the corpus striatum as well as in the hippocampus. The chief interest is to design a pharmacological therapy for both disorders with Cdk5 as its target, with the clear possibility of a clinical application in the treatment of patients with Huntington's and other neurological diseases.

This project proposes to:

  • Determine the molecular mechanisms by which Cdk5 increases striatal vulnerability in knock-in murine models of HD.
  • Analyse the role of Cdk5 in synaptic plasticity and cognitive deficits in knock-in murine models of HD, validating Cdk5 as a therapeutic target in HD.
  • Examine the efficacy of drugs which directly or indirectly inhibit the Cdk5 route to delay, improve or reverse motor and/or cognitive deficits in knock-in murine models of HD.


  • Dopaminergic activation via the D1 dopamine receptor induces more death in striate cells that express mutated huntingtin than in those that express wild-type huntingtin.
  • The increased susceptibility to dopaminergic activation of mutated cells is associated with greater mitochondrial fragmentation.
  • The greater mitochondrial fragmentation observed in mutated cells is induced by an aberrant activation of Cdk5 kinase, given that the pharmacological inhibition of Cdk5 totally prevents mitochondrial fragmentation and with this, cell death.
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