Parkinson's disease and other movement disorders
Parkinson's disease (PD) is the second most frequent neurodegenerative disease with a progressively higher incidence and prevalence given the increase in life expectancy. The typical clinical manifestations are motor (tremor, clumsiness, rigidity, etc.) and are mainly caused by the degeneration of the dopaminergic system. Current treatments are symptomatic and focus on restoring this dopamine deficiency. However, the causes of the disease are unknown, so there are no therapies capable of preventing the progression of dopaminergic loss or the spread of neurodegeneration to other neuronal populations. This causes other clinical manifestations among which dementia is one of the most important. Furthermore, a relevant aspect is that when the diagnosis of PD is made, more than half of the dopaminergic neurons have degenerated.
Our main objectives are:
1. To know the causes and mechanisms of neuronal degeneration in order to find therapeutic targets that prevent or delay the development of the disease.
2. To identify new biomarkers for early diagnosis and for monitoring the evolution of the disease.
For this objective, various approaches are developed, combining clinical studies in patients and subjects at risk of developing the disease with preclinical experimental studies in various animal models and in cell cultures. The approach is multidisciplinary, comprising neurophysiological, molecular, cellular, biochemical, genetic, imaging studies, etc., providing a translational approach with synergies between the different fields.
Specifically, our projects are aimed at:
Study cellular and molecular mechanisms associated with neurodegeneration
One of the objectives is to identify new modulators of neuronal death that may constitute effective therapeutic targets for neurodegenerative diseases. To do this, we use automated microscopy technology in which we monitor the activation of cell pathways of interest using fluorescent reporters. This technology has been developed in our laboratory and allows longitudinal studies of neuronal survival in primary cultures in which we apply regression models of predictive variables of neuronal, autonomous and non-autonomous death.
Specifically, we study the contribution of the over-expression, aggregation and post-translational modifications of proteins (such as synuclein, superoxide dismutase or the amyloid precursor protein) involved in synucleinopathies, Amyotrophic Lateral Sclerosis and Alzheimer's disease in neuronal death. In collaboration with Dr. Tomás Aragón (link / web page), we study the function of the activation of the cellular pathway of the Unfolded Protein Response (UPR) in these neurodegenerative processes.
IP: Montse Arrasate
Another objective is the characterization of the inflammatory response that occurs in brain regions affected by dopaminergic degeneration in Parkinson's disease and the effect of the endocannabinoid system on the modulation of neuroinflammation. The ultimate objective is the design of new neuroprotective treatments acting on the microglial and / or astroglial activation associated with the neurodegenerative process.
IP: Marisol Aymerich
Develop neuroprotection strategies with gene therapy by glucocerebrosidase over expression
Mutations in the GBA1 gene, that codes for an enzyme in the lysosome called glucocerebrosidase, constitute the main genetic risk factor for Parkinson's disease. These mutations decrease the enzymatic activity of glucocerebrosidase, which is associated with accumulation and intracellular deposits of alpha-synuclein.
Studies of our group have shown that the use of viral vectors carrying the GBA1 gene increase glucocerebrosidase levels and clear the synuclein aggregates in both rodents and non-human primates, preventing death of dopaminergic neurons and decreasing the reactive responseof microglial cells, thus, minimizing the progression of alpha-synuclein pathology. Our work focuses on using gene therapy to increase glucocerebrosidase expression to attenuate or even stop the progression of the disease.
IP: Jose Luis Lanciego
> European AND-PD Consortium
Our laboratory participates in the European consortium AND-PD (Mechanisms of Comorbidity of Parkinson's disease and anxiety), as part of a joint effort that brings together 11 European institutions, including universities, research centers and biotechnology-based companies.
The project aims to investigate the pathological mechanisms causing anxiety and depression that are observed as comorbid entities in more than 40% of Parkinson's patients.
Identify synaptic disorders associated with neurodegeneration
Our work focuses on the sequential study of the synaptic functional and structural alterations that occur in dopaminergic projections to the striatum, frontal cortex, and hippocampus in a model of progressive parkinsonism induced by alpha-synuclein overexpression in the SNc. The ultimate goal is to identify therapeutic targets in order to stop the process of synaptic degeneration and neuronal death associated with motor deficit and cognitive decline in Parkinson's disease. For this purpose, we use histology techniques (immunohistochemistry and immunofluorescence), confocal and optical microscopy, image analysis (quantification by stereology and optical density), synaptosome isolation, western blot, metabolic assays (Seahorse XF96) and flow cytometry.
IP: Maria Cruz Rodriguez-Oroz
Study the physiology and neuromodulation of brain circuits
Parkinson's disease results in alterations in brain activity associated with both the typical clinical manifestations of the disease and treatments. Our objective is to identify these alterations to develop neuromodulation therapies aimed at restoring brain dynamics.
To do this, we use methodologies that cover a broad spectrum of recording and neuromodulation modalities in patients, including electrocencephalography (EEG), electromyography (EMG), electrocorticography (ECoG), and records in deep structures (subthalamic nucleus). At the preclinical level, we use animal models in which we combine these electrophysiological records with in-vivo neuromodulation technologies such as optogenetics, chemogenetics, and intelligent stimulation (close-loop).
IP: Miguel Valencia, Julio Artieda
Identify biomarkers using omics, imaging and liquid biopsy techniques
The objective is to identify surrogate markers of Parkinson's disease that allow its diagnosis in the symptomatic and prodromal phase and the monitoring of its progression. For them, we combine brain PET studies to evaluate dopaminergic denervation and brain metabolism, structural and functional MRI, marker analysis in cerebrospinal fluid and plasma.
IP: Maricruz Rodriguez-Oroz, Rosario Luquin