RESEARCH

RESEARCH INTERESTS

mTOR is a serine/threonine kinase that coordinates anabolic and catabolic processes in the cell as a response to extracellular events such as nutrient levels, energy availability, or stress situations. mTOR and its signaling 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 arborization, 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 tumors, 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 with Parkinson's disease, Huntington's disease, Alzheimer's disease, neural plasticity, and development.

RESEARCH LINES

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 all 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. In the R6/1 mouse model of HD, synaptic RTP801 contributed to motor-learning dysfunction. In the R6/1 mouse model, striatal RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium-permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity.

References:

1. Martín-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.

2. Martín-Flores N, Pérez-Sisqués L, Creus-Muncunill J, Masana M, Ginés S, Alberch J, Pérez-Navarro E, Malagelada C. Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease. Cell Death Dis. 2020 Jul 30;11(7):569. doi: 10.1038/s41419-020-02775-5.


A novel role of RTP801 in Alzheimer's disease (AD)?


Our predoctoral student, Leticia Pérez-Sisqués, in collaboration with the group of Dr. Albert Giralt, is investigating whether RTP801 is involved in AD pathology and inflammation.


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 with PD.  Moreover, we found that SNPs in the mTOR pathway and in the SNCA gene interacted to modulate the risk of age at onset for 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).

References: 

1. 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, 2018, doi: 10.1007/s12035-018-1219-1.

2. 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 Sep;34(9):1333-1344. doi: 10.1002/mds.27770. Epub 2019 Jun 24.



PUBLICATIONS FROM THE LAB:

  • Martín-Flores N, Pérez-Sisqués L, Creus-Muncunill J, Masana M, Ginés S, Alberch J, Pérez-Navarro E, Malagelada C. Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease. Cell Death Dis. 2020 Jul 30;11(7):569. doi: 10.1038/s41419-020-02775-5.
  • Creus-Muncunill J, Badillos-Rodríguez R , Garcia-Forn M, Masana M, Garcia-Díaz Barriga G, Guisado-Corcoll A, Alberch J, Malagelada C, Delgado-García JM, Gruart A, Pérez-Navarro E. Increased translation as a novel pathogenic mechanism in Huntington's disease. Brain. 2019 Oct 1;142(10):3158-3175
  • Fernández-Santiago R, Martín-Flores N, Antonelli F, Cerquera C, Moreno V,  Bandres-Ciga S, Manduchi E, Tolosa E, Singleton A, Moore JH, The International Parkinson's Disease Genomics Consortium (IPDGC), Martí MJ, Ezquerra M & Malagelada C. SNCA and mTOR pathway SNPs interact to modulate the age-at-onset of Parkinson's disease. Movement Disorders 2019 Sep;34(9):1333-1344
  • 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 (2018), doi: 10.1007/s12035-018-1219-1.
  • 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.

  • 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.
  • Martín-Flores N, Romaní-Aumedes J, Rué L, Canal M, Sander P, Straccia M, Allen N, Alberch J, Canals JM, Pérez-Navarro E, Malagelada C. RTP801 is involved in mutant huntingtin-induced cell death. Mol. Neurobiol (2015), doi: 10.1007/s12035-015-9166-6.
  • 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), doi 10.3389/fncel.2014.00313.
  • 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; doi:10.1038/cddis.2014.333.t.