Neurometabolic Diseases Lab

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Lines of Research
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X-linked Adrenoleukodystrophy as a paradigm of neurometabolic disease.

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, 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.

Pathophysiology of Pelizaeus Merzbacher, Metachromatic Leukodystrophy and beyond.

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.

Comparative insight in the peroxisomal proteome and metabolome.

The peroxisome is an essential organelle ubiquitously present in eukaryotic cells and organisms, playing a key role in lipid metabolism, free radical detoxification, glycolisis, bile acids and penicillin biosynthesis, and other functions. In humans, loss of peroxisomes invariably leads to fatal peroxisome biogenesis disorders (PBD) such as Zellweger syndrome. We have used a high throughput comparative genomics analysis to elucidate the evolutionary origin of the organelle, to find out that the peroxisomal membrane is derived from ER membranes. However, the different metabolic routes that integrate the organelle of modern organisms, might have prokaryotic ancestors and are currently being studied. These and other results are integrated in our public database www.peroxisomeDB.org, which assembles data from clinical, metabolic and genomic resources, allowing automated functional genomics searches through in-house developed high-throughput tools.

 

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