The aging of the population poses a growing burden in society. This is associated with the increase in disability and diseases that have a high impact on health care, on patients and their families. Likewise, aging is associated with the appearance of different neurodegenerative diseases, among which include frontotemporal dementia (FDT), 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 FTD, PD and ALS.

Amyotrophic lateral sclerosis (ALS): Analysis of RNA transport and protein translation in situ: implication of STAUFEN 1/2?
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the spinal cord and cerebral cortex. Patients have a loss of muscle strength and coordination that progressively progresses, preventing the performance of daily activities. Until now there is no treatment that cures ALS, and for this reason in our laboratory we are developing several lines of research that aim to address this challenge by designing and developing new therapies for the treatment of ALS. One of the main characteristics of ALS is that there are alterations in mRNA metabolism and deregulated axonal transport. For this reason, in a project financed by FUNDELA, we are determining if the TDP-43 aggregates kidnap the RNA-binding proteins, and do not let them carry out their function, in such a way that the mRNAs do not reach the synaptic connections and cannot be translate, causing there to be no connection between the neuron and the muscle, which ultimately leads to loss of muscle function. So, we are looking at RNA granule transport and protein translation in situ in ALS, determining the involvement of STAUFEN and TDP-43 proteins.

Frontotemporal dementia: Research on therapies to modulate neurodegeneration-associated TDP-43 and TAU proteins
Frontotemporal dementia (FTD) is an early-onset, progressive neurodegenerative disease characterized by primarily neuronal degeneration in the frontal and temporal lobes followed by hippocampal atrophy. FTD is the second cause of dementia in adult patients and the most frequent in patients under 65 years of age. From the molecular point of view, FTD is characterized mainly by aggregates of TAU or TDP-43 proteins. There is also dysregulation of redox homeostasis and low-grade chronic neuroinflammation. Currently, there is no approved effective treatment for FTD that could modulate the course of the disease. In recent years, we identify the transcription factor NRF2 as a key factor to limit neurodegenerative process. NRF2 has a very broad spectrum of action in different cellular processes. Therefore, our aim is to repurpose the use of dimethyl fumarate for the treatment of patients with FTD, either TAU or TDP-43, and think that it would be of great benefit to these patients who currently lack treatment to slow down the degenerative process.

Modulation of cannabinoid CB2 receptor as a new therapeutic strategy to protect against TAU-dependent FTD neurodegeneration
The TAU protein is the main component of the intracellular filamentous deposits that define a series of neurodegenerative diseases called tauopathies. In general, tauopathies are characterized by alterations in synaptic plasticity, cell death, proteinopathy, and neuroinflammation. Despite enormous efforts to find a cure for these diseases, there is still no effective treatment. That is why in my laboratory we face this challenge with two different approaches. In our laboratory we have shown in vitro and in vivo that neurons with accumulation of TAU induce the expression of the cannabinoid receptor CB2, which enhances neurodegeneration. Therefore, in a first approach we focus on the study of the pharmacological modulation of the CB2 receptor and its effects on TAU-induced neurodegeneration, with a project funded by the Fundación Tatiana Pérez de Guzmán el Bueno (2021-2024). There are currently no specific biomarkers for tauopathies that allow a prognosis/diagnosis of these diseases.

Differential function of mitochondria in neuron-astrocyte-dependent α-synuclein protein in Parkinson's disease
Parkinson's disease (PD) is the most prevalent neurodegenerative disease with motor disturbances characterized by degeneration of dopaminergic (DA) neurons of the substantia nigra and accumulation of protein aggregates in the so-called Lewy bodies, where the most abundant protein is alpha-synuclein (α-SYN). In addition to the neurodegenerative process and protein accumulation, PD is characterized by chronic low-grade inflammation and oxidative stress, which are associated with mitochondrial alterations. PD has been predominantly approached from a neuron-centered point of view, without taking into consideration other cell types, such as astrocytes, which are part of the tripartite synapse. But we cannot rule out that mitochondrial dynamics and function may also be altered in astrocytes and differently from DAergic neurons, contributing to the onset and spread of the disease. Therefore, in this research project we aim to address the hypothesis that mitochondrial dynamics and function may be different between neurons and astrocytes in α-SYN-associated PD.