The "leaky" activity of mutant enzymes is the basis of neurodegenerative diseases

Spinal cerebellar ataxia is a group of neurodegenerative diseases characterized by degenerative degeneration of Purkinye cells, a major neuron in the cerebellum
.
The resulting cerebellar dysfunction causes patients to lose motor coordination and control
.
A subtype of the disease, type 14 spinal cerebellar ataxia SCA14), was found to be caused by mutations in the protein kinase C-γ (PKCγ), an enzyme
that regulates other proteins in Pukenye cells.
But exactly how these mutations alter the function of enzymes and ultimately lead to neurodegenerative degeneration is unknown
.

In a new study published on September 27, 2022, researchers at the University of California, San Diego School of Medicine found that SCA14-related mutations disrupt the self-inhibition and degradation of PKC γ, leading to elevated
levels of enzyme activity.
This constant "leakage" activity alters the phosphate group of Pukenye's cells, thereby driving cerebellar pathology
.

"Our findings reveal an important mechanism of spinal cerebellar disorders and position PKC gamma as a promising therapeutic target for this neurodegenerative disease," said senior author Alexandra C.
Newton, Ph.
D.
, Distinguished Professor of Pharmacology at
the University of California, San Diego School of Medicine.

To understand how SCA14-related mutations affect the enzyme's function, the researchers first measured the activity levels
of different PKC gamma variants in cultured cells.
Compared with the more common PKCγ variants, the enzymatic activity of PKCγ with SCA14 mutations in the C1A and C1B domains of the protein was significantly enhanced, and further experiments confirmed that this was due to conformational changes that disrupted the autoinhibition and degradation
of the enzyme.

Self-inhibition is a field regulatory mechanism in which certain domains in the molecular structure act on their own function
.

The researchers then found that the enhancement of PKC gamma activity led to a cascade of downstream changes in the phosphorylation state of the cellular environment, particularly signaling pathway dysregulation
associated with axial bursts and cytoskeleton structures.

The degree of interruption of PKC gamma self-inhibition is related to the severity of the disease, and mutations that induce particularly high levels of PKC gamma activity are also associated
with the early age of onset of the disease.

PKCγ itself is regulated by intracellular calcium, and many other types of spinal cerebellar ataxia are driven by mutations that affect calcium
homeostasis.
Therefore, the authors suggest that targeting PKCγ may correct this broader signaling pathway and demonstrate efficacy
in the treatment of multiple forms of disease.

Newton said: "This opens up exciting possibilities
for therapeutic spinal cerebellar ataxia targeting not only in SCA14, but also in many other subtypes.
"

Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition