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New therapeutic approach discovered for the neurodegenerative disease BPAN

The study, carried out by a research team from the Andalusian Center for Developmental Biology, shows that biotin reactivates the inactive X chromosome and improves cell functions in models of this disease / The research opens new perspectives for other X-linked diseases.



From above, from left to right, Diana Reche López, Paula Cilleros Holgado, Alejandra López Cabrera y José Manuel Romero Domínguez. Abajo, de izquierda a derecha, David Gómez Fernández, Ana Romero González, Raquel García-Salas, José Antonio Sánchez Alcázar, Mónica Álvarez Córdoba y Rocío Piñero Pérez. Author: JM Ramos_fotografías

A research team from the Andalusian Center for Developmental Biology (CABD) has identified an innovative mechanism that could open new therapeutic avenues for the neurodegenerative disease BPAN (Beta-Propeller Protein-Associated Neurodegeneration). The study, led by Professor of Cell Biology at Pablo de Olavide University José Antonio Sánchez Alcázar and published in the International Journal of Molecular Sciences, shows that biotin, a nutrient with epigenetic properties, can reactivate the inactive X chromosome and restore altered cell functions in models of this disease.

BPAN is a rare X-linked genetic disorder that causes an abnormal accumulation of iron in the brain and severely affects the nervous system. Its symptoms include recurrent seizures, intellectual disability, developmental delay, ataxia and parkinsonism. Currently, there is no curative treatment, and the available options only partially alleviate the symptoms.

Reactivating the X chromosome to restore cellular functions

The CABD team has discovered that biotin is able to restore the expression of the WDR45 gene, whose mutation causes the disease. This process occurs through histone biotinylation, an epigenetic mechanism that favors the reactivation of the inactive X chromosome, allowing the functional allele of the gene to be expressed again. The results show a remarkable improvement in iron homeostasis, mitochondrial bioenergetics and the autophagic capacity of the cells, key aspects in the development of BPAN.


Biotin induces reactivation of the inactive X chromosome and corrects pathophysiological alterations in beta-helix protein-associated neurodegeneration

According to Dr. Sánchez Alcázar, “our results indicate that reactivation of the inactive X chromosome not only represents a new therapeutic avenue for BPAN, but could also be applied to other genetic diseases linked to this chromosome, such as Rett syndrome or Fragile X syndrome”.

The research has been possible thanks to the support of patient associations such as 'Camina con Lola', 'Gabriella mi pequeña guerrera' and 'BPAN Spain', as well as the Fundación Bancaria Unicaja.

Another step forward in personalized medicine

This finding is part of the BrainCure Project, an initiative that since 2014 has been committed to personalized medicine for neurodegenerative diseases with iron accumulation. The team evaluates treatments in patient-derived cellular models, allowing the most effective options to be selected prior to their possible clinical application. Currently, this approach is being used with more than 40 patients from different countries, including Spain, Brazil, Mexico and the United States.

The BrainCure Project is performing precision medicine in the 5 most frequent subtypes: PKAN, pantothenate kinase-associated neurodegeneration, with mutations in the PANK2 gene; PLAN, PLA2G6-associated neurodegeneration, with mutations in the PLA2G6 gene; BPAN, beta-propeller protein-associated neurodegeneration, with mutations in the WDR45 gene; MPAN, mitochondrial membrane protein-associated neurodegeneration, with mutations in the C19orf12 gene; and FAHN, fatty acid hydroxylase-associated neurodegeneration, with mutations in the FA2H gene.

Reference:

Reche-López D, Romero-González A, Álvarez-Córdoba M, Suárez-Carrillo A, Cilleros-Holgado P, Piñero-Pérez R, Gómez-Fernández D, Romero-Domínguez JM, López-Cabrera A, González-Granero S, García-Verdugo JM, Sánchez-Alcázar JA. Biotin Induces Inactive Chromosome X Reactivation and Corrects Physiopathological Alterations in Beta-Propeller-Protein-Associated Neurodegeneration. Int. J. Mol. Sci.  2025.  doi: 10.3390/ijms26031315