Monday, 18th December 2017


Molecular Neuropatholohy

   Huntington's disease and other CNS disorders




José Lucas




Research summary:

In our laboratory we are focused on understanding the molecular mechanisms of neural diseases with an emphasis on generation of conditional mouse models (like the HD94 Huntington's model -Cell 101:57-66, 2000 cited 702 times- or the Tet/GSK3 Alzheimer's model -EMBO J. 20:27-39, 2001 cited 614 times-) to validate pathogenic pathways and to test new therapeutic strategies.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by involuntary movements, psychiatric symptoms and dementia. It is caused by an expansion of the trinucleotide CAG located in exon 1 of the huntingtin gene.

In recent years we have demonstrated an imbalance in two tau isoforms and discovered a new histopathological hallmark (the Tau Nuclear Rods or TNRs). The use of transgenic HD mouse models with varying levels of tau demonstrated that tau contributes to HD pathogenesis (Nat Med 20(8):881-5, 2014). This discovery relates HD with tauopathies, which include Alzheimer's disease, thus broadening the possible therapies applicable to HD to those generated for tauopathies.

We have also explored the role of GSK-3 in various neural conditions like HD (Cell Death Differ. 17:324-35, 2010; Hum Mol Genet. 24(17):5040-52, 2015). Regarding the possible neuroprotective effect of GSK-3 inhibitors, we found that besides the reported antiapoptotic effect, inhibition of GSK-3 can also be proapoptotic in certain paradigms and cell types (including striatal neurons) and that the underlying mechanism involves NFAT and FAS (J Clin Invest. 120:2432-45, 2010).

Fig02-300 --------- Fig01-300
Expression of the transcription factor ATF5 in neurons of the hypocampus from mice  .........

COS cells tranfected with Green Fluorescent protein (GFP)



Relevant publications:


Fernández-Nogales M, Hernández F, Miguez A, Alberch J, Ginés S, Pérez-Navarro E and Lucas JJ (2015) Decreased Glycogen Synthase Kinase-3 levels and activity contribute to Huntington's Disease. Hum Mol Genet doi:10.1093/hmg/ddv224

Fernández-Nogales M, Cabrera JR, Santos-Galindo M, Hoozemans JJM, Ferrer I, Rozemuller AJM, Hernández F, Avila J and Lucas JJ (2014) Huntington's disease is a four-repeat tauopathy with tau-nuclear rods. Nat Med 20, 881-885.

Torres-Peraza JF, Engel T, Martín-Ibáñez R, Sanz-Rodríguez A, Fernández-Fernández MR, Esgleas M, Canals JM, Henshall DC and Lucas1 JJ (2013) Protective neuronal induction of ATF5 in endoplasmic reticulum stress induced by status epilepticus. Brain 136:1161-76.

Engel T, Sanz-Rodgriguez A, Jimenez-Mateos EM, Concannon CG, Jimenez-Pacheco A, Moran C, Mesuret G, Petit E, Delanty N, Farrell MA, O'Brien DF, Prehn JH, Lucas JJ, Henshall DC. (2013) CHOP regulates the p53-MDM2 axis and is required for neuronal survival after seizures. Brain. 2013 Feb;136(Pt 2):577-92. doi: 10.1093/brain/aws337.

Gómez-Sintes, R. and Lucas, J.J. (2010) NFAT/Fas-signaling mediates apoptosis and neurological side-effects of GSK-3-inhibition in a mouse model of lithium therapy. J. Clin. Invest. 120, 2432-45.


Other activities:

- Grupo integrante del Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)

- José Lucas nombrado Académico Correspondiente de la Real Academia Nacional de Farmacia, Junio de 2011.