Cell and Molecular Neurobiology of Parkinson's Disease (Neurolab)
The Cell and Molecular Neurobiology of Parkinson’s Disease group investigates the cellular and molecular mechanisms underlying dopaminergic neurodegeneration, with a particular focus on the brain renin–angiotensin system (RAS) as both a driver of pathology and a therapeutic target. We were the first to demonstrate that central RAS dysregulation drives oxidative stress, neuroinflammation, mitochondrial dysfunction, and neurovascular impairment, as well as to identify autoimmune mechanisms mediated by autoantibodies against RAS components, showing how these antibodies chronically amplify microglial activation and enhance dopaminergic vulnerability. Leveraging extensive expertise in Parkinson’s disease modeling, the group has elucidated multiple pathogenic factors and translated these findings into neuroprotective strategies that improve dopaminergic neuron survival in preclinical models. A highly innovative research line focuses on the in vitro generation of dopaminergic neurons from neural stem cells and iPSCs, enabling cell replacement therapy, mechanistic studies, and drug discovery, while reducing reliance on animal models. The group also investigates the pathophysiology of L-DOPA–induced dyskinesias and develops early biomarkers of neurodegeneration, crucial for intervention before irreversible neuronal loss occurs.
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Basic research in Parkinson's disease
Our group has extensive expertise in developing and applying advanced experimental models of Parkinson's disease (PD), all fully established and operational in our laboratory. These models reproduce key pathological features of the disorder, enabling detailed investigation of its molecular mechanisms and those of related neurodegenerative diseases. Using these approaches, we have identified major contributors to PD progression, including oxidative stress, mitochondrial dysfunction, neuroinflammation, genetic mutations, protein aggregation, impaired autophagy, and neuronal toxicity.
Development of neuroprotective strategies
Leveraging our models, we routinely implement targeted interventions that improve dopaminergic neuron survival. These capabilities provide a solid basis for translational studies and the development of clinically relevant therapeutic strategies.
Brain renin -angiotensin system
We have fully established methodologies to investigate the brain renin -angiotensin system (RAS) in PD. Our research has shown its involvement in dopaminergic neuron degeneration and protection via oxidative stress regulation, inflammatory signaling, and mitochondrial function. Given its role in PD and its association with metabolic syndrome and COVID-19, the RAS is a promising therapeutic target in our research pipeline.
Mutant and misfolded alpha-synuclein
We have all the necessary tools to study the pathogenic role of mutant and misfolded alpha-synuclein, a hallmark of PD. Our models allow detailed analysis of their aggregation, protein interactions, and the resulting cellular dysfunction that leads to neuronal death.
In vitro generation of dopaminergic neurons
Our laboratory routinely generates dopaminergic neurons from neural stem cells and induced pluripotent stem cells (iPSCs). These cells are valuable for disease modeling, drug discovery, and cell replacement strategies, reducing reliance on animal models and enabling refinement of PD modeling and therapeutic development. We are also advancing stem cell -based approaches to restore neuronal populations lost to the disease.
Dyskinesias
We actively investigate dyskinesias using validated experimental systems that reproduce these involuntary movements, often induced by current PD treatments. We aim to clarify their underlying mechanisms and develop strategies to prevent or mitigate their onset.
Early markers of Parkinson's disease
We have implemented ultrasensitive analytical tools to detect early molecular and cellular markers of neurodegeneration, crucial for timely neuroprotective interventions. This is particularly relevant given that PD motor symptoms usually appear only after approximately 80% of dopaminergic terminals are lost.
Membros
Publicacións seleccionadas
Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms. Neurotherapeutics.
Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson's disease models
AT1 receptor autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability
Angiotensin type-1 receptor and ACE2 autoantibodies in Parkinson's disease
An ACE2/Mas-related receptor MrgE axis in dopaminergic neuron mitochondria
Rho kinase inhibitor fasudil reduces l-DOPA-induced dyskinesia in a rat model of Parkinson's disease.
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