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

Research summary:

We study the molecular mechanisms of neural diseases by generating genetic mouse models (like the HD94 Huntington’s model Cell 101:57-66 2000 cited 806 times, the Tet/GSK3 Alzheimer’s model EMBO J 20:27-39 2001 cited 733 times, or the TgCPEB4Δ4 model of idiopathic autism Nature 560:441-446 2018) 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 the huntingtin gene.
 
In recent years we have demonstrated in HD an alteration of tau (the protein that accumulate inside neurons in Alzheimer’s disease) and discovered a new histopathological hallmark (the Tau Nuclear Rods or Tau Nuclear Indentations). 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 cited 112 times). This discovery relates HD with tauopathies, like Alzheimer’s disease, thus broadening the application of new therapies being developed for these diseases. 
 
While characterizing the role of cytoplasmic polyadenylation on translational control in HD, we discovered that the majority of autism spectrum disorder (ASD) risk genes are targets of CPEB4. In fact, CPEB4 shows an isoform imbalance in individuals with autism due to mis-splicing of a neuronal specific microexon. Accordingly, mice with equivalent CPEB4 imbalance show autism-like phenotype (Nature 560:441-446, 2018) and have become a useful model of idiopathic autism.
 
Recently, we have also described an alteration of cytoplasmic polyadenylation in epilepsy (Brain 143: 2139-53 2020) and the pathogenic role of altered splicing in Huntington's (Nat Med. 20: 881-5 2014; Brain 143: 2207-19 2020; Brain in press 2021). 
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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
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:

  • Elorza A, Marquez Y, Cabrera JR, Sanchez-Trincado JL, Santos-Galindo M, Hernandez IH, Diaz-Hernandez JI, Garcia-Escudero R, Irimia M and Lucas JJ (2021) Huntington’s disease-specific mis-splicing unveils key effector genes and altered splicing factors. Brain (in press) BioRxiv preprint: doi.org/10.1101/2020.05.11.086017
  • 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 143:2207-19
  • 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 143:2139-53
  • 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 560:441-6
  • 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. 134:839-50
  • McKinnon C, Goold R, Andre R, Devoy A, Ortega Z, Moonga J, Linehan JM, Brandner S, Lucas JJ, Collinge J and Tabrizi SJ. (2015) Prion-mediated neurodegeneration associated with early impairment ofubiquitin-proteasome system. Acta Neuropathol. 131:411-25
  • 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, 881-5
  • Torres-Peraza JF, Engel T, Martín-Ibañez R, Fernández-Fernández MR, Esgleas M, Canals JM, Henshall DC & Lucas JJ (2013) Protective neuronal induction of ATF5 in endoplasmic reticulum stress induced by status epilepticus. Brain 136:1161-76
  • Gomez-Sintes R and Lucas JJ (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
  • Maynard CJ, Böttcher C, Ortega Z, Smith R, Florea BI, Diaz-Hernandez M, Brundin P, Overkleeft H, Li JY, Lucas JJ & Dantuma N (2009) Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment. PNAS 106:13986-91
  • Gómez-Sintes R, Hernández F, Bortolozzi A, Artigas F, Avila J, Zaratin P, Gotteland J-P & Lucas JJ (2007) Neuronal apoptosis and reversible motor deficit in dominat-negative GSK-3 conditional transgenic mice. EMBO J. 26: 2743-54
  • Lucas JJ, Hernández F, Gómez-Ramos P, Morán MA, Hen R, and Avila J (2001). Decreased nuclear ß-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3ß conditional transgenic mice. EMBO J. 20, 27-39
  • Yamamoto A*, Lucas JJ* & Hen R (2000) *These authors contributed equally to the work. Reversal of neuropathology and motor dysfunction in a conditional model of Huntingtron´s Disease. Cell 101: 57-66

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