Neurometabolic Diseases Lab

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Lines of Research
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1-Traslational Research for X-adrenoleukodystrophy: from molecular basis of disease to clinical trials

X-ALD is a rare disease caused by mutations in the Abcd1 gene, encoding a peroxisomal transporter of fatty acids. Its biochemical hallmark is the intracellular accumulation of very-long-chain fatty acids (VLCFAs). Using the mouse model of the disease, we applied a transcriptomic analysis, which combined with redox proteomics, metabolomics, lipidomics, epigenomics, plus biochemical, molecular and cellular biology techniques has unveiled key dysregulated metabolic routes and signalling pathways, previously unrelated to the pathology.

Our major current interests can be organized as follows: i) dissecting the role of fatty acid accumulation as inducers of oxidative stress and mitochondria malfunction; ii) applying a systems approach to integrate transcriptomics, proteomics, metabolomics and lipidomics data in kinetic prediction models in silico . This will allow pinpointing key, druggable pathways that will be tested in primaryneural culture models; iii) identifying neural cell autonomous versus non-cell autonomous mechanisms of toxicity driven by fatty acids excess; iv) translate the knowledge into preclinical tests in the mouse model of the disease, which will pave the way for developing novel therapeutic strategies.

2- Genomic Medicine for the leukodystrophies: clinical genomics for diagnosis and novel gene identification

We aim at diagnosis and novel gene discovery for brain white matter disorders through clinical genomics technology (whole exome and genome sequencing).  We are identifying disease-causing variants in known genes thanks to novel developed algorithms and pipelines, and  interpreting the clinical significance for diagnostic reporting. Moreover, we are identifying novel disease-causing genes and modeling disease using iPS-derived organoid cultures and zebrafish. Results are advancing scientific knowledge while serving the undiagnosed community.

3- Pathophysiology of Pelizaeus Merzbacher, Metachromatic Leukodystrophy and other neurometabolic diseases

The bioinformatics and experimental set up techniques used to investigate adrenoleukodystrophy will be applied to the analysis of  other rare white matter neurodegenerative diseases, such as Pelizaeus Merzbacher and Metachromatic Leukodystrophy. Our research might have an impact on the most prevalent neurodegenerative diseases that undergo with oxidative stress linked to metabolic disturbances, and on the cognitive impairment associated to aging.

A systems biology approach will allow discerning between common events to various degenerative processes, and disease-specific disturbances. Further, a systems approach will allow discriminating primary from secondary pathogenic events in the neurodegenerative cascade. This is of paramount importance for facilitating the rational design of pharmacological strategies.


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