Spinocerebellar ataxias are a group of neurodegenerative diseases characterized by the degeneration of Purkinje cells, a major class of neurons in the cerebellum. The resulting cerebellar dysfunction causes patients to lose coordination and motor control.
A subtype of the disease, spinocerebellar ataxia type 14 (SCA14), has been found to be caused by mutations in protein kinase C-gamma (PKCγ), an enzyme that regulates other proteins in Purkinje cells. But exactly how these mutations alter the function of the enzyme to ultimately lead to neurodegeneration remained unknown.
In a new study, published September 27, 2022 in the journal . Science Signaling, researchers at the University of California, San Diego School of Medicine found that mutations associated with SCA14 syndrome disrupt PKCγ self-inhibition and degradation, resulting in elevated levels of enzyme activity . This sustained and “leaky” activity modifies the phosphoproteome of Purkinje cells and leads to cerebellar pathology.
Our results reveal important mechanisms that underlie spinocerebellar ataxia and position PKCγ as a promising therapeutic target for this neurodegenerative disease. »
Alexandra C. Newton, PhD, lead author, Distinguished Professor of Pharmacology, UC San Diego School of Medicine
To understand how mutations associated with SCA14 affect the function of the enzyme, the researchers first measured the activity levels of different PKCγ variants in cultured cells. Compared to the more common PKCγ variants, those with SCA14 mutations in the C1A and C1B domains of the protein showed significantly increased enzyme activity, which further experiments confirmed to be due to conformational changes that impede self-inhibition and enzyme degradation.
Self-inhibition is a regulatory mechanism in place in which certain domains of the structure of a molecule act to suppress its own function.
The researchers then found that the increased activity of PKCγ leads to a cascade of downstream changes in the phosphorylation state of the cellular environment, in particular the dysregulation of signaling pathways involved in the development of axons and the structure of the cytoskeleton. .
The extent of disrupted PKCγ autoinhibition was correlated with disease severity, and mutations that induced a particularly high level of PKCγ activity were also associated with an earlier age of disease onset.
PKCγ is itself regulated by intracellular calcium, and many other types of spinocerebellar ataxia are due to mutations that affect calcium homeostasis. Thus, the authors suggest that targeting PKCγ could correct this broader signaling pathway and prove effective in the treatment of several forms of the disease.
“This raises exciting possibilities for therapeutically targeting PKCγ not only in SCA14 but also in many other subtypes of spinocerebellar ataxia,” Newton said.
Source :
University of California–San Diego
Journal reference:
Pilo, CA, et al. (2022) Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing self-inhibition of kinases. Science Signaling. doi.org/10.1126/scisignal.abk1147.