June 17, 2021

New neurodegeneration culprit

A young woman with a puzzling neurological illness and novel genetic variant pointed investigators to a role for dysregulated protein kinase D1 in neurodegeneration.

Presented with the case of a young woman with a novel de novo genetic variant and a puzzling neurological illness, Eric Delpire, PhD, and colleagues saw aspects of the disease recapitulated in miniature when they used CRISPR to engineer the variant in mice.  

The team’s report, appearing in Clinical Genetics, uncovers a neurodegenerative disease role for dysregulated protein kinase D1 (PKD1), a hardworking biomolecule previously implicated in certain cancers and cardiovascular disorders. The discovery introduces a potential therapeutic target in diseases that affect myelin, the fatty substance surrounding nerve cell axons. 

The genetic variant in question (in the gene PRKD1) has rendered PKD1 inactive. Among other neurological symptoms, the patient has epileptic seizures and chronic peripheral neuropathy. 

Using a cell line, the team established that PKD1 affects the activity of KCC3, a cotransporter previously implicated in sensorimotor neuropathy and brain hyperexcitability. This connection is likely at play in neurodegenerative effects of PKD1 dysregulation, the authors conclude.

On the study also from VUMC are Salma Omer and Rainelli Koumangoye, PhD. They were joined by researchers at Yale University. The study was supported in part by the National Institutes of Health (DK093501).