Neurodegeneration and signaling. PI: Cristina Malagelada Grau

Presentation

mTOR is a serine/threonine kinase that coordinates anabolic and catabolic processes in the cell as a response to extra cellular events such as nutrient levels, energy availability or stress situations. mTOR and its signalling pathways have been described mainly in proliferative non-neuronal cells. Therefore, the role that mTOR plays in differentiated cells as neurons is not very clear. There is evidence of mTOR as a modulator of survival, differentiation and development of neurons. It is also a key player in axonal growth, dendritic arborisation and synaptogenesis. In the adult brain, mTOR has been implicated in physiologic processes like neural plasticity, learning or memory. Moreover, its activity can be altered in pathological processes including tuberous sclerosis, Alzheimer's disease, Parkinson's disease, brain tumours and cortical dysplasia.

Our main research line is the study of mTOR and one of its main modulators, the protein RTP801/REDD1, in neurodegeneration associated to Parkinson's disease, Huntington's disease, neural plasticity and development.

For more details about our activities, you can click the next link: http://www.malagelada-lab.eu/

 

Cristina Malagelada Grau
Associate professor
cristina.malagelada@ub.edu

 

Núria Martín-Flores
Doctorate student
nmartifl7@alumnes.ub.edu

 

Leticia Pérez-Sisqués
Doctorate student
leticiaperezsisques@ub.edu

 

Arnau Llobet Rosell
Master's student
allobero8@alumnes.ub.edu

 

Júlia Solana Balaguer
Predoctoral FPU scholarship
julia.solbal@gmail.com

 

Genís Campoy Campos
Master's student
geniscampoy@hotmail.com

  • RTP801 regulation of mTOR signaling in Parkinson's disease (PD)

RTP801 is a stress-regulated protein that is sufficient and necessary to induce neuron death. It is elevated in cellular and animal models of PD in response to dopaminergic neurotoxins such as 6-Hydroxydopamine (6-OHDA) and MPP+/MPTP, and induces neuron death by a sequential inactivation of mTOR and the survival kinase Akt. Indeed, RTP801 is highly up regulated in neuromelanin positive neurons in the SNpc of both sporadic and parkin mutant PD patients. Moreover Rapamycin an inhibitor of most but not al mTOR activities was protective in cellular and animal models of PD by decreasing the levels of RTP801.  Hence, our main objective is to understand the role of RTP801 in neurodegeneration associated with PD. For this reason we have been studying RTP801 turnover. During their theses, Dr. Joan Romaní-Aumedes found that RTP801 can be ubiquitinated by parkin for proteasomal degradation.  Dr. Mercè Canal also found NEDD4 is able to ubiquitinate RTP801 to mediate its lysosomal degradation.

References:

  1. Ryu EJ, Angelastro JM, Greene LA. Analysis of gene expression changes in a cellular model of Parkinson disease. Neurobiol Dis. 2005 Feb;18(1):54-74.PMID: 15649696
  2. Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA. RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation. J Neurosci. 2006;26(39):9996-10005.
  3. Malagelada C, Zong HJ, Greene LA. RTP801 is induced in Parkinson's disease and mediates neuron death by inhibiting Akt phosphorylation/activation. J Neurosci. 2008;28(53).
  4. Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J Neurosci. 2010;30(3):1166-1175.
  5. Romaní-Aumedes J, Canal M, Martín-Flores N, Pérez-Fernández V, Wewering S, Fernández-Santiago R, Ezquerra M, Pont-Sunyer C, Lafuente A, Alberch J, Luebbert H, Tolosa E, Greene LA, Malagelada C. Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease. Cell Death and Disease (2014) 5, e1364;
  6. Canal M, Martín-Flores N, Pérez-Sisqués L, Romaní-Aumedes J, Atlas B., Man HY, Kawabe H, Alberch J, Malagelada C. Loss of NEDD4 contributes to RTP801 elevation and neuron toxicity: implications for Parkinson's disease. (Oncotarget 2016, August 2; 7(37):58813-58831).
  • A novel role of RTP801 in Huntington's disease (HD)

Our predoctoral student, Núria Martín-Flores, in collaboration with the group of Dr. Esther Pérez-Navarro and Dr. Jordi Alberch found that RTP801 is up regulated in HD human brains and in differentiating neurons derived from induced Pluripotent Stem Cells (iPSC) from HD patients. More importantly, in cellular models of HD, RTP801 mediated mutant huntingtin toxicity in neurons.

References:

  1. Martin-Flores N, Romani-Aumedes J, Rue L, et al. RTP801 Is Involved in Mutant Huntingtin-Induced Cell Death. Mol Neurobiol. 2015. doi:10.1007/s12035-015-9166-6.
  • mTOR signaling modulation of Levodopa-induced dyskinesia

L-DOPA-induced dyskinesia (LID) is the major invalidating adverse effect of chronic administration of L-DOPA, which is the only dopamine (DA) substitutive treatment currently available in PD. Susceptibility to LID is largely variable in patients, and its modulating factors are not yet elucidated. Currently, we are investigating which discriminatory single nucleotide polymorphisms (SNPs) in the genes of the mTOR pathway are associated with LID in subjects diagnosed of PD.  This is a project funded in 2014 by the Michael J. Fox Foundation and some of the results have been patented. This project is being developed  by teaming up with neurologist Dr. Maria Josep Martí and Dr. Eduard Tolosa (Hospital Clínic) and the geneticists Dr. Mario Ezquerra and Dr. Rubén Fernández-Santiago (IDIBAPS).

  • Title: ¿La proteína RTP801/REDD1 media la disfunción sináptica en procesos neurodegenerativos?

Researcher of the team that participates in the project: Cristina Malagelada Grau
Project reference: SAF2017-88812-R
Principal investigator: Cristina Malagelada Grau
Funding entity: MINECO. Durada: 01/01/2018-31/12/2020
Funding received (in euros): 145.200. Project status: granted

  • Title: Modulación de la plasticidad sináptica como estrategia terapéutica en la enfermedad de Huntington

Researcher of the team that participates in the project: Cristina Malagelada Grau
Project reference: SAF2014-57160-R
Principal investigator: Jordi Alberch Vié and Cristina Malagelada Grau
Funding entity: MINECO. Period: 01/01/2015-31/12/2017
Funding received (in euros): 270.000,00. Project status: granted

  • Title: LRRK2 peripheral blood mononuclear cells and urine biosample collection

Researcher of the team that participates in the project: Cristina Malagelada Grau
Principal investigator: Dr. Maria Josep Martí and Dr. Eduard Tolosa
Funding entity: Michael J. Fox Foundation. Period: 01/01/2016-31/12/2018
Funding received (in euros): 152.000,00. Project status: granted

Title registered industrial property: Method for predicting early onset and severity of levodopa induced dyskinesia (LID) in subjects diagnosed of Parkinson disease (PD)

Type of industrial property: Inventory patent
Inventors/authors/obtenidors: Cristina Malagelada Grau; Núria Martín Flores; Maria Josep Martí Domènech; Rubén Fernández Santiago; Mario Ezquerra Trabalón
Entity holder of rights: Universitat de Barcelona
Application number: EP17382248.7
Registration date: 04/05/2017
International Patent No. EU: Yes

Title registered industrial property: Métodos para predecir síntomas extrapiramidales

Type of industrial property: Inventory patent
Inventors/authors/obtenidors: Mas, S.; Gassó, P.; Malagelada, C.; Lafuente, A.; Bernardo, M.
Entity holder of rights: Universitat de Barcelona
Registration Country: Spain
Companies: Universitat de Barcelona; IIBB/IDIBAPS/CSIC
- Patent number: EP13382027. Registration date: 2013. Date of concession: 2013, Spanish patent: Yes
- Application number: EP 13382027.4. Registration date: 25/01/2013, International Patent No. EU: Yes
- Application number: US14/763292 Fecha de registro: 24/07/2015. International Patent No. EU: Yes;  PCT Patent: Yes
- Application number: EP14701206.6. Country of priority: Member countries of the European Patent Convention. Priority date: 25/08/2015
Exclusive patent licensing agreement: Universitat de Barcelona
Number of researchers: 5, Mas, S.; Gassó, P.; Malagelada, C.; Lafuente, A.; Bernardo, M
Participating entities: Universitat de Barcelona
Financing entities: AB-Biòtics, S.A. 08290 Cerdanyola del Vallès, España

For more information for PI publications click in the link:
ORCID: https://orcid.org/0000-0001-7185-436X
ResearcherID: http://www.researcherid.com/rid/A-6101-2012

Fernández-Santiago R, Martín-Flores N, Antonelli F, Cerquera C, Moreno V, Bandres-Ciga S, Manduchi E, Tolosa E, Singleton AB, Moore JH; International Parkinson's Disease Genomics Consortium, Martí MJ, Ezquerra M, Malagelada C. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease. Mov Disord. 2019 Jun 24. doi: 10.1002/ mds.27770. [Epub ahead of print] PMID: 31234232

Martín-Flores N, Fernández-Santiago R, Antonelli F, Cerquera C, Moreno V, Martí MJ, Ezquerra M, Malagelada C. MTOR Pathway-Based Discovery of Genetic Susceptibility to L-DOPA-Induced Dyskinesia in Parkinson's Disease Patients.Mol Neurobiol. 2019 Mar;56(3):2092-2100. doi: 10.1007/s12035-018-1219-1. Epub 2018 Jul 10.PMID: 29992529.

Creus-Muncunill J, Rué L, Alcalá-Vida R, Badillos-Rodríguez R, Romaní-Aumedes J, Marco S, Alberch J, Perez-Otaño I, Malagelada C, Pérez-Navarro E. Increased Levels of Rictor Prevent Mutant Huntingtin-Induced Neuronal Degeneration. Mol Neurobiol. 2018 Oct;55(10):7728-7742. doi: 10.1007/s12035-018-0956-5. Epub 2018 Feb 19. PMID: 29460266.

Saavedra A, Fernández-García S, Cases S, Puigdellívol M, Alcalá-Vida R, Martín-Flores N, Alberch J, Ginés S, Malagelada C, Pérez-Navarro E. Chelerythrine Promotes Ca(2+)-dependent calpain activation in neuronal cells in a PKC-independent manner. Biochim Biophys Acta. 2017 Apr;1861(4):922-935. doi: 10.1016/j.bbagen.2017.01.021. Epub 2017 Jan 24. PubMed PMID: 28130160.

Canal M, Martín-Flores N, Pérez-Sisqués L, Romaní-Aumedes J, Altas B, Man HY, Kawabe H, Alberch J, Malagelada C. Loss of NEDD4 contributes to RTP801 elevation and neuron toxicity: implications for Parkinson's disease. Oncotarget. 2016 Sep 13;7(37):58813-58831. doi: 10.18632/oncotarget.11020. PubMed PMID: 27494837; PubMed Central PMCID: PMC5312278.

Martín-Flores N, Romaní-Aumedes J, Rué L, Canal M, Sanders P, Straccia M, Allen ND, Alberch J, Canals JM, Pérez-Navarro E, Malagelada C. RTP801 Is Involved in Mutant Huntingtin-Induced Cell Death. Mol Neurobiol. 2016 Jul; 53(5):2857-2868. doi: 10.1007/s12035-015-9166-6. Epub 2015 Apr 16. PubMed PMID: 25876513.

Canal M, Romaní-Aumedes J, Martín-Flores N, Pérez-Fernández V, Malagelada C. RTP801/REDD1: a stress coping regulator that turns into a troublemaker in neurodegenerative disorders. Front Cell Neurosci. 2014 Oct 2;8:313. doi: 10.3389/fncel.2014.00313. eCollection 2014. Review. PubMed PMID: 25324725; PubMed Central PMCID: PMC4183088.

Romaní-Aumedes J, Canal M, Martín-Flores N, Sun X, Pérez-Fernández V, Wewering S, Fernández-Santiago R, Ezquerra M, Pont-Sunyer C, Lafuente A, Alberch J, Luebbert H, Tolosa E, Levy OA, Greene LA, Malagelada C. Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease. Cell Death Dis. 2014 Aug 7;5:e1364. Doi: 10.1038/cddis.2014.333. PubMed PMID: 25101677; PubMed Central PMCID: PMC4454308.

Sun X, Liu J, Crary JF, Malagelada C, Sulzer D, Greene LA, Levy OA. ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin. J Neurosci. 2013 Feb 6;33(6):2398-407. doi: 10.1523/ JNEUROSCI. 2292-12.2013. PubMed PMID: 23392669; PubMed Central PMCID: PMC3711618.

Greene LA, Levy O, Malagelada C. Akt as a victim, villain and potential hero in Parkinson's disease pathophysiology and treatment. Cell Mol Neurobiol. 2011 Oct;31(7):969-78. doi: 10.1007/s10571-011-9671-8. Epub 2011 Mar 10. PubMed PMID: 21547489; PubMed Central PMCID: PMC3678379.

Malagelada C, López-Toledano MA, Willett RT, Jin ZH, Shelanski ML, Greene LA. RTP801/REDD1 regulates the timing of cortical neurogenesis and neuron migration. J Neurosci. 2011 Mar 2;31(9):3186-96. doi: 10.1523/ JNEUROSCI. 4011-10.2011. PubMed PMID: 21368030; PubMed Central PMCID: PMC3089438.

  • Offers from the University of Barcelona:

Work UB

  • Offers from the Research Group:

At the moment, there are no job offers from this Research Group

 

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