Molecular basis of Huntington's disease and other central nervous system disorders

Research summary:

We are interested on the molecular mechanisms of neural diseases. We focus on in vivo studies by generating and characterizing genetic mouse models that faithfully mimic neural diseases (like the HD94 Huntington’s model Cell 101:57-66 2000 cited 788 times, the Tet/GSK3 Alzheimer’s model EMBO J 20:27-39 2001 cited 708 times, or the TgCPEB4Δ4 model of idiopathic autism Nature 560:441-446 2018): This way we can validate pathogenic pathways and preclinically 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 our laboratory we have demonstrated an imbalance in two isoforms of tau (one of the key proteins that aggregate in Alzheimer’s disease brains) and discovered a new histopathological hallmark (the Tau Nuclear Rods or TNRs). By analyzing transgenic HD mouse models with varying levels of tau we demonstrated that tau contributes to HD pathogenesis (Nat Med. 2014, 20:881-5). This discovery relates HD with tauopathies, which include Alzheimer’s disease, thus broadening the possible therapies applicable to HD to those generated for tauopathies.

While characterizing the role of cytoplasmic polyadenylation on translational control in the brain, we recently discovered that the majority of autism spectrum disorder (ASD) risk genes are targets of CPEB4. Accordingly, CPEB4 shows an isoform imbalance in individuals with autism due to mis-splicing of a neuronal specific microexon and an equivalent imbalance in mice induces autism-like phenotype (Nature 560:441-446, 2018).

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Tau Nuclear Rods (TNRs) in neurons of an HD patient.

 
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Expression of the transcription factor ATF5 in mouse hippocampal neurons.

 
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Last nameNameLaboratoryExt.*e-mailProfessional category
Elorza PeregrinaAinara2094582aelorza(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Hernández HernándezIvo2094582ihernandez(at)cbm.csic.esEstancia/CIBER
Lozano MuñozDavid2094552dlozano(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Lucas LozanoJosé Javier2094552jjlucas(at)cbm.csic.esE. Profesores de Investigación de Organismos Públicos de Investigación
Lucas SantamaríaMiriam2094582mmlucas(at)cbm.csic.esContratado CIBER
Ollá Ivana2094582ivanaolla(at)cbm.csic.esContratado CIBER
Picó del PinoSara2094582sara.pico(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Rodríguez LópezClaudia2094582crodriguez(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Santos GalindoMaría2094582msantos(at)cbm.csic.esE. Técnicos Superiores Especializados de Organismos Públicos de Investigación

Relevant publications:

  • Hernández IH, Cabrera JR, Santos-Galindo M, Sánchez-Martín M, Domínguez V, García-Escudero R, Pérez-Álvarez MJ, Pintado B and Lucas JJ (2020) Pathogenic SREK1 decrease in Huntington’s disease lowers TAF1 mimicking X-linked dystonia parkinsonism. Brain (in press)
  • Parras A, de Diego-Garcia L, Alves M, Beamer E, Conte G, Jimenez-Mateos EM, Morgan J, Ollà I, Hernandez-Santana Y, Delanty N, Farrell MA, O’Brien DF, Ocampo A, Henshall DC, Méndez R, Lucas JJ* and Engel T* (2020) mRNA polyadenylation as a novel regulatory mechanism of gene expression in temporal lobe epilepsy. Brain (in press)
  • Parras A, Anta H, Santos-Galindo M, Swarup V, Elorza A, Nieto-González JL, Picó S, Hernández IH, Díaz-Hernández JI, Belloc E, Rodolosse A, Parikshak NN, Peñagarikano O, Fernández-Chacón R, Irimia M, Navarro P, Geschwind DH, Méndez R, Lucas JJ. (2018) Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing. Nature 560:441-446
  • Hernández IH, Torres-Peraza J, Santos-Galindo M, Ramos-Morón E, Fernández-Fernández MR, Pérez-Álvarez MJ, Miranda-Vizuete A, Lucas JJ. (2017) The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington's disease. Acta Neuropathol. 134:839-850
  • 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

Other activities:

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