DDX11 protein that "cleans" cells: hope for rare and neurodegenerative diseases

A study conducted by the Institute of Biochemistry and Cell Biology of the National Research Council in Naples (CNR-Ibbc) has unveiled a hitherto unknown function of DDX11, a DNA helicase, i.e., a protein specialized in opening the DNA double helix to allow its replication and repair. The discovery opens new perspectives in the understanding and possible treatment of rare genetic diseases, such as Warsaw Breakage Syndrome, and neurodegenerative disorders such as Parkinson's and Alzheimer's.

The research, led by the group headed by Francesca M. Pisani, research executive at CNR-Ibbc, and published in the journal Autophagy, is a collaboration with Maurizio Renna of the Department of Molecular Medicine and Medical Biotechnology at the University of Naples Federico II.

"The DDX11 protein is mutated in patients with Warsaw Breakage Syndrome (WABS), a rare genetic disorder that impairs physical and neurodevelopment," says Francesca M. Pisani (CNR-Ibbc). "WABS belongs to the group of cohesinopathies, rare genetic diseases caused by alterations in the cohesin protein complex or its regulatory proteins, which are essential for cell division to occur properly." Precisely because of its involvement insister chromatid cohesion during cell division, DNA helicase DDX11has been the focus of previous studies by the CNR-Ibbc research group.

The new experiments allowed the Cnr-Ibbc team to discover that the DDX11 protein is also active in the cytoplasm of our cells, where it directly intervenes in the regulation of autophagy, the process by which damaged and no longer functioning organelles and proteins are recycled. "We observed that in the absence of DDX11, cells lose the ability to properly form autophagosomes, the 'shuttles' that transport cellular waste to lysosomes for degradation," explains Raffaella Bonavita, first author of the study. "This impairs the removal of toxic aggregates such as those containing the mutated huntingtin protein associated with Huntington's Korea."

Another key finding from the study concerns the interaction between DDX11 and the p62/SQSTM1 protein, a receptor critical for sorting and loading proteins and impaired organelles into autophagosomes. "Cells derived from patients with WABS also show altered autophagy flux, reinforcing the hypothesis that autophagy malfunction contributes to the pathology," continues Raffaella Bonavita. Autophagy is now considered an essential mechanism for nervous system health, and its disruption has been linked to numerous neurodegenerative diseases, including Parkinson's, Alzheimer's, ALS and ataxia with oculomotor apraxia type 2 (AOA2).

The direct involvement of DDX11 in this process opens up entirely new perspectives. "Understanding how DDX11 regulates autophagy could prove decisive not only for understanding the molecular basis of WABS, but also for the future development of therapeutic strategies against neurodegenerative disorders," concludes Francesca M. Pisani.

The work was carried out with the support of the European project CohesiNet, dedicated to cohesin biology and cohesinopathies, and the national project CNCCS-B (FOE - CNR), focused on rare diseases.