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.
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.
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.
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.
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.
mTOR signaling modulation of Levodopa-induced dyskinesia
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).
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.
PUBLICATIONS FROM THE PREDOCTORAL STUDENTS IN THE LAB:
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), (in press)
- 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.
- 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.