New therapeutic strategies in neurodegenerative diseases: Parkinson's disease, tauopathies and amyotrophic lateral sclerosis

Introduction

The aging of the population poses a growing burden in society. This is associated with an increase in disability and diseases that have a high impact on health care, on patients and their families. Also, aging is associated with the emergence of different neurodegenerative diseases among which include Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Therefore, the development of advanced biological markers, new drugs and appropriate technology is the key to establishing a treatment for these diseases, which is currently an important social challenge. In our laboratory we study the molecular basis of neurodegeneration. The research projects we develop have a multidisciplinary approach that combines basic and translational research, using cell culture techniques, murine models and postmortem samples from patients with AD, PD and ALS.

Currently, our research is focused on addressing three key aspects of neurodegeneration:

1) Proteinopathy: the accumulation of beta-amyloid plaques and neurofibrillary tangles of TAU protein, involved in neurodegeneration processes, appear in AD. In the case of PD, the alpha-synuclein protein plays a key role in the degeneration of dopaminergic neurons, forming part of the Lewy bodies. And in ALS there is alteration of RNA metabolism and homeostasis. Recent work that connects TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves the aggregation of proteins as part of their normal function, is altered in ALS. We are interested in determining the role of these proteins in the neurodegeration process.

2) Inflammation: it is a process that appears in the first stages of the disease and aggravates neurodegeneration. Alzheimer's and Parkinson's diseases are characterized by what is called chronic low-grade inflammation, so we want to determine what causes this inflammation and how it can be prevented or stopped.

3) Oxidative stress: it is imbalance between the production of reactive oxygen species and the ability of a biological system to quickly decode the intermediate reagents or repair the resulting damage. It has been observed that this imbalance is present in these neurodegenerative diseases, so we want to study what it is that causes it and how to reverse it.

RECENT PUBLICATIONS

1: Galán-Ganga M, García-Yagüe ÁJ, Lastres-Becker I. Role of MSK1 in the Induction of NF-κB by the Chemokine CX3CL1 in Microglial Cells. Cell Mol Neurobiol. 2019 Mar 4. doi: 10.1007/s10571-019-00664-w. [Epub ahead of print]PubMed PMID: 30830503.

2: Castro-Sánchez S, García-Yagüe ÁJ, Kügler S, Lastres-Becker I. CX3CR1-deficient microglia shows impaired signalling of the transcription factor NRF2: Implications in tauopathies. Redox Biol. 2019 Feb 6;22:101118. doi:10.1016/j.redox.2019.101118. [Epub ahead of print] PubMed PMID:30769286; PubMed Central PMCID: PMC6375000

3: Castro-Sánchez S, García-Yagüe ÁJ, López-Royo T, Casarejos M, Lanciego JL, Lastres-Becker I. Cx3cr1-deficiency exacerbates alpha-synuclein-A53T induced neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease. Glia. 2018 Apr 6. doi: 10.1002/glia.23338. [Epub ahead of print] PubMed PMID: 29624735.

4: Cuadrado A, Kügler S, Lastres-Becker I. Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy. Redox Biol. 2018 Apr;14:522-534. doi: 10.1016/j.redox.2017.10.010. Epub 2017 Nov 6. PubMed PMID: 29121589; PubMed Central PMCID: PMC5681345.

5: Lastres-Becker I. Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights. J Alzheimers Dis Parkinsonism 2017, 7:4. DOI: 10.4172/2161-0460.1000340

6: Lastres-Becker I*, Nonis D, Eich F, Klinkenberg M, Gorospe M, Kötter P, Klein FA, Kedersha N, Auburger G*. Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation. Biochim Biophys Acta. 2016 Sep;1862(9):1558-69. doi: 10.1016/j.bbadis.2016.05.017. PubMed PMID: 27240544; PubMed Central PMCID: PMC4967000.

7: Lastres-Becker I*, García-Yagüe AJ, Scannevin RH, Casarejos MJ, Kügler S, Rábano A, Cuadrado A*. Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease. Antioxid Redox Signal. 2016 Jul 10;25(2):61-77. doi: 10.1089/ars.2015.6549. PubMed PMID: 27009601; PubMed Central PMCID: PMC4943471.

8: Fittschen M*, Lastres-Becker I*, Halbach MV, Damrath E, Gispert S, Azizov M, Walter M, Müller S, Auburger G. Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decrease translation rate. Neurogenetics. 2015 Jul;16(3):181-92. doi: 10.1007/s10048-015-0441-5. PubMed PMID: 25721894; PubMed Central PMCID: PMC4475250.

9: Cuadrado A, Martín-Moldes Z, Ye J, Lastres-Becker I. Transcription factors NRF2 and NF-κB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation. J Biol Chem. 2014 May 30;289(22):15244-58. doi:10.1074/jbc.M113.540633. PubMed PMID: 24759106; PubMed Central PMCID: PMC4140883.

10: Lastres-Becker I*, Innamorato NG, Jaworski T, Rábano A, Kügler S, Van Leuven F, Cuadrado A*. Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis. Brain. 2014 Jan;137(Pt 1):78-91. doi: 10.1093/brain/awt323. PubMed PMID: 24277722.

11: Lastres-Becker I*, Ulusoy A, Innamorato NG, Sahin G, Rábano A, Kirik D, Cuadrado A*. α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease. Hum Mol Genet. 2012 Jul 15;21(14):3173-92. doi: 10.1093/hmg/dds143. PubMed PMID: 22513881.

12: Kurz A, Double KL, Lastres-Becker I, Tozzi A, Tantucci M, Bockhart V, Bonin M, García-Arencibia M, Nuber S, Schlaudraff F, Liss B, Fernández-Ruiz J, Gerlach M, Wüllner U, Lüddens H, Calabresi P, Auburger G, Gispert S. A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice. PLoS One. 2010 Jul 7;5(7):e11464. doi: 10.1371/journal.pone.0011464. PubMed PMID: 20628651; PubMed Central PMCID: PMC2898885.

FUNDINGS Our laboratory receives funding from various national and international sources, including:

1: Health Research Foundation 2000 in neurodegenerative diseases (2013) for the project: Characterization of the proteasome and autophagy degradation system in an AAV6-a-synuclein model of Parkinson's disease: involvement of the transcription factor Nrf2 (2013-2014). PI: Isabel Lastres-Becker.

2: NRF2 role as an antioxidant modulator neuroinflammation in Alzheimer's disease. This work was supported by Spanish Ministerio de Ciencia e Innovacion Grant SAF2013-43271-R (2013-2016). PI: Antonio Cuadrado/Isabel Lastres-Becker.

3: Advanced theranostic approach in cancer combining photodynamic therapy and nanoparticles. This work was supported by M.ERA-NET (01-06-2016-31-05-2020). PI: Antonio Cuadrado. Co-investigator: Isabel Lastres-Becker.

4: European network of centers of excellence-COEN (2013-2015) Wnt signaling: biomarker and target evaluation in Alzheimer’s disease. PI: Antonio Cuadrado. Co-investigator: Isabel Lastres-Becker.

5: Targeting NRF2 with BG-12 to modify Parkinson’s disease progression in the AAV6-alpha-synuclein mouse model founded by Biogen Iberica (2013-2015). PI: Antonio Cuadrado. Co-investigator: Isabel Lastres-Becker.

6: Role of NRF2 in the function and fate of the Alzheimer's brain. This work is supported by Spanish Ministerio de Ciencia e Innovacion Grant SAF2016-76520-R (2017-2020). PI: Antonio Cuadrado/Isabel Lastres-Becker.

7: Design and development of innovative drugs for the treatment of amyotrophic lateral sclerosis. Conserjería de educación e investigación de la Comunidad de Madrid B2017/BMD-3813 ELA-Madrid (2018-2021). PI: Ana Martínez/Isabel Lastres-Becker

8: European network of centers of excellence-COEN (2018-20120) Developing preclinical and clinical biomarkers of NRF2 pathway activation for therapeutic application in neurodegenerative diseases. PI: Pamela Shaw. Co-investigator: Isabel Lastres-Becker.

AWARDS

1: Scientific Achievement Award for the oral presentation: Effect of Tetrahydrocannabinol in Animal Models of Huntington’s disease. 12th International Cannabinoid Research Society, Symposium on the Cannabinoids 10-14 Julio del 2002, Pacific Grove, CA, USA

2: Prize of the Spanish Society of Cannabinoid Research (SEIC) for the best publication on cannabinoids in 2003 for the article entitled: Compounds acting at the endocannabinoid and/or endovanilloid systems reduce hyperkinesia in a rat model of Huntington’s disease. Published in Journal of Neurochemistry 84, 1097-1109 (2003).

3: Award Juan Abelló Pascual II 2003 for the PhD thesis entitle: Implication of the endogenous cannabinoid system in extrapyramidal neurodegenerative diseases. (Real Academia de Doctores)

4: IBRO travel award (2004) for the FENS-meeting

5: Extraordinary award for the PhD Thesis (2002-2003) in the Complutense University.

6: Research award L'Oreal-Unesco for women in science en November 2010.


Lastres Becker, Isabel
Profesor Contratado Doctor



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