Parkinson's Disease

PI: Montse Arrasate y Marisol Aymerich

Objectives:

• To identify new modulators of neuronal death that constitute effective therapeutic targets for neurodegenerative diseases. For this purpose, we use an automated microscopy technology in which we monitor the activation of cellular pathways of interest by means of fluorescent reporters. This technology has been developed in our laboratory and allows us to perform 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 expression, aggregation and post-translational modifications of proteins involved in synucleinopathies, Amyotrophic Lateral Sclerosis and Alzheimer's disease (such as synuclein, superoxide dismutase or amyloid precursor protein) in neuronal death. In collaboration with Dr. Tomás Aragón (link/ web page) we studied the role of the activation of the Unfolded Protein Response pathway in these neurodegenerative processes.
• Characterization of the type of inflammatory response of brain regions affected by dopaminergic degeneration in Parkinson's disease and the effect of the endocannabinoid system in modulating neuroinflammation. The ultimate goal is the design of new treatments that act on the microglial and/or astroglial activation associated with the neurodegenerative process for its prevention.

PI: José Luis Lanciego

Mutations in the GBA1 gene coding for a lysosomal enzyme called glucocerebrosidase are the main genetic risk factor for Parkinson's disease. These mutations cause the enzymatic activity of glucocerebrosidase to be greatly diminished, 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 can increase glucocerebrosidase levels and clear synuclein aggregates in both rodents and non-human primates, preventing cell death of dopaminergic neurons, decreasing the reactive response of microglial cells and minimizing the progression of alpha-synuclein pathology.

Objectives:

• Our work focuses on using glucocerebrosidase gene therapy to attenuate or even halt the progressive course that characterizes this neurodegenerative disease.

AND-PD European Consortium

Our laboratory participates in the European AND-PD (Comorbidity mechanisms of anxiety and Parkinson's disease) consortium, as part of a joint effort involving 11 European institutions, including universities, research centers and biotechnology-based companies.

The project aims to investigate the pathological mechanisms causing the anxiety and depression that are typically observed as comorbid entities in more than 40% of Parkinsonian patients. 

PI: Mª Cruz Rodríguez-Oroz

Objectives:

• Sequential study of the functional and structural synaptic alterations that occur in the dopaminergic projections to the striatum, frontal cortex and hippocampus in a model of progressive parkinsonism due to overexpression of alpha-synuclein in the SNc.
• To identify therapeutic targets in order to stop the process of synaptic degeneration and neuronal death associated with motor deficit and cognitive impairment in Parkinson's disease. For this purpose we use histology techniques (immunohistochemistry and immunofluorescence), optical and confocal microscopy, image analysis (quantification by stereology and optical density), synaptosome isolation, western blot, metabolic assays (Seahorse XF96) and flow cytometry.

PI: Miguel Valencia, Julio Artieda

Parkinson's disease gives rise to alterations in brain activity associated with both the typical clinical manifestations of the disease and treatments.

Objectives:

• To identify such alterations in order to develop neuromodulation therapies aimed at restoring brain dynamics.To this end we use methodologies covering a wide spectrum of recording and neuromodulation modalities in patients including electroencephalography (EEG), electromyography (EMG), electrocorticography (ECoG) and recordings in deep structures (subthalamic nucleus). At the preclinical level we employ animal models in which we combine these electrophysiological recordings with in-vivo neuromodulation technologies such as optogenetics, chemogenetics and close-loop stimulation.

PI: Mª Cruz Rodríguez-Oroz, Rosario Luquin

Objectives:

• To identify surrogate markers of Parkinson's disease that allow its diagnosis in symptomatic and prodromal phase and the monitoring of its progression. We combine brain PET studies to evaluate dopaminergic denervation and brain metabolism, structural and functional MRI, analysis of markers in cerebrospinal fluid and plasma.