Molecular Neurobiology - Universidad Autónoma de Madrid

Molecular Neurobiology
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D7
Huntington’s disease and other CNS disorders
Research summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG triplet
repeat expansion coding for a poly-glutamine (polyQ) sequence in the N-terminal region of the huntingtin (htt)
protein. However, the precise mechanism by which mutant-huntingtin elicits its toxicity remains unknown.
We were pioneers in applying conditional transgenesis in mice to study neurodegeneration. This technology
allows exploring what aspects of neuropathology are susceptible to revert upon shut down of the pathogenic
transgene. The conditional mouse model of HD revealed that disease may be reversible (Cell 101: 57-66,
2000) even in advanced stages after neuronal loss has taken place (J. Neurosci. 25, 9773-9781; 2005).
Research summary
Staff
Publications
Regarding the molecular mechanisms by which mutant huntingtin induces pathology, we have explored the
ubiquitin proteasome system (UPS) hypothesis in brain samples (J. Neurosci. 23, 11653-61, 2003), in vitro
with purified aggregates (J. Neurosci. 24, 9361-71, 2004; J. Neurochem. 98, 1585-1596; 2006) and in vivo
by using UPS impairment reporter mice (Trends Neurosci. 27, 66-69, 2004). Concerning the mechanisms
of synaptic dysfunction in HD, we have detected changes in the physiology of the P2X7 ATP-gated calcium
channel (J. Cell Sci. 121: 3717-28, 2008 and FASEB J. in press). Finally, we have also explored the potential
role of the GSK-3 kinase as therapeutic target in HD and its role in the physiology of striatal neurons (EMBO
J. 26: 2743-2754, 2007).
Other activities
Patents
CBM 2007-2008