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Propionic acidemia: impact on the epigenome and the proteome in relation to the cardiac and neurological phenotype

20th national competition for scientific and technical research

Rare diseases

Senior Researcher : Eva María Richard Rodríguez

Research Centre or Institution : Centro de Biología Molecular Severo Ochoa. CSIC - UAM


Our group performs translational studies to generate and characterize relevant animal and cellular models for specific inherited metabolic diseases, rare diseases with an unmet clinical need to improve existing therapies. The main objective of this project is to study the specific pathophysiological mechanisms that contribute to the progression of cardiomyopathy and neurological alterations in propionic acidemia (PA), which are the main causes of mortality and morbidity in this disease. In this period, the following results have been obtained: 1) in the liver of the hypomorphic animal model of PA, an increase in histone H4 propionylation has been observed compared to control mice. The histone acyltransferase MOF has been identified as responsible for this post-translational modification and SIRT3 histone deacylase that would eliminate it. Likewise, by RNA-seq, a series of over-expressed genes have been identified, such as Ppargc1A involved in mitochondrial biogenesis.   

Next, the study of brain samples from the animal model of PA will be carried out. 2) in cardiomyocytes derived from iPSC lines of patients with PA compared to controls we have observed: a mitochondrial dysfunction (caused by lower mitochondrial oxygen consumption, and increased levels of ROS and antioxidant proteins), increased lipid vesicles and autophagosomes, increased levels of proteins involved in mitochondrial biogenesis, increased oxidative stress of the endoplasmic reticulum, and deregulation in the expression of miRNAs. Next, astrocyte differentiation from iPSC lines will be carried out. Our work has deepened our understanding of the affected cellular pathways and the molecular mechanisms that contribute to the pathophysiology of PA with the aim of advancing in the identification of new therapeutic targets in this devastating neurometabolic disease.


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Communications at international conferences 1


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