Elevated Enzyme Activity Detected; Discovery Could Help Treat Neurodegenerative Disease [Study]

In new research published recently, researchers at the University of California San Diego School of Medicine discovered that SCA 14-associated mutations are disrupting the autoinhibition and degradation of PKCγ, resulting in elevated levels of enzyme activity.

In relation to this discovery, a UC San Diego report described spinocerebellar ataxias as "a group of neurodegenerative diseases" characterized by the Purkinje cells' degeneration. These cells are a major class of neurons present in the cerebellum.

Essentially, the resulting cerebellar dysfunction is leading patients to experience a loss of motor coordination and control. One subtype of this disease, as earlier described, the spinocerebellar ataxia type 14 or SCA 14, was discovered to be resulting from mutations by PKCγ or protein kinase C-gamma.

PKCγ is an enzyme that's regulating other proteins present in Purkinje cells. However, precisely how such mutations are changing the function of the enzyme to eventually drive neurodegeneration remained unknown.

Purkinje Cell Phosphrogeome

What has been described in the study published in the Science Signaling journal as "sustained leaky activity" is changing the Purkinje cell phosphoproteome to drive cerebellar pathology.

According to Alexandra Newton, Ph. D., the study's senior author and distinguished Professor of Pharmacology at UC San Diego School of Medicine, their findings show "important mechanisms" that underlie spinocerebellar ataxia and position PKCγ as a potential therapeutic target for this neurodegenerative condition.

To understand how SCA14-associated mutations are affecting the function of the enzyme, researchers measured the activity levels of different variants of PKCγ in cultured cells.

Compared to more common PKCγ variants, those that have SCA14 mutations in the C1A and C1B domains of the protein reveal substantially enhanced enzymatic activity, which further experiments verified was because of conformational changes that damage the autoinhibition and degradation of the enzyme.

'Autoinhibition'

A similar Medical Xpress report describes autoinhibition as an "on-site regulatory mechanism" in which certain domains within the structure of a molecule function to repress its own function.

The study investigators then discovered the enhanced PKCγ activity resulted in a cascade of downstream alterations to the phosphorylation state of the cellular environment, specifically dysregulating signaling pathways engaged in axon development and cytoskeletal structure.

The level of disrupted PKCγ autoinhibition correlated with the severity of the diseases, and mutations that induced a specifically high PKCγ activity level were linked to an earlier age of disease onset, as well.

Potential for Therapeutically Targeting PKCγ

PKCγ is itself controlled by intercellular calcium, as well as many other spinocerebellar ataxia types are driven by a mutation that impacts calcium homeostasis.

Therefore, the researchers suggest that targeting PKCγ may address the broader signaling pathway and prove efficacy in treating multiple forms of the disease.

This brings exciting probabilities for therapeutically targeting PKCγ not just in SCA14 but in many other subtypes of spinocerebellar ataxia, explained Newton.

The study was financially backed, partly by the National Institutes of Health, the Zionic Ataxia Fund, and the National Ataxia Foundation.

Related information about neurodegenerative diseases is shown on UBengineering's YouTube video below:

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