In a recent search for gene variants associated with Alzheimer’s disease (AD), several affected families showed a mutation in an enzyme called protein kinase C-alpha (PKCα). Family members with this mutation had AD; those without the mutation did not.
The M489V mutation has since been shown to increase the activity of PKCα by a modest 30 percent, so if and how it contributes to the neuropathology of AD has remained unclear.
In a new study, researchers found that the subtle increase in PKCα was sufficient to produce biochemical, cellular and cognitive impairments in mice, similar to those observed in human AD. The findings, published in Nature Communications, position PKCα as a promising therapeutic target for the disease.
PKCα regulates the function of many other proteins, particularly in the brain. The enzyme facilitates chemical reactions that add phosphate groups to other proteins, shaping their activity and ability to bind to other molecules. By tuning the phosphorylation state of proteins in the synaptic environment, PKCα may play an important role in synaptic function and neuronal signaling.
To assess its role in AD, several research teams collaborated to first generate a mouse model with the PKCα M489V mutation and then assess its biochemistry and behavior over the next year and a half (corresponding to approximately 55 years in human aging).
After three months, the brains of the mutated mice had significantly altered levels of protein phosphorylation compared to the brains of wild type control mice, indicating that neuronal proteins were being misregulated. By 4.5 months, the mice’s hippocampal neurons showed several cellular changes, including synaptic depression and reduced density of dendritic spines. By 12 months, the mice showed impaired performance in behavioral tests of spatial learning and memory, clear evidence of cognitive decline.
“We were surprised to find that just a slight increase in PKCα activity was enough to recreate the Alzheimer’s phenotype in a mouse,” said senior author. “This is an amazing example of the importance of homeostasis in biology — even minor tweaks in kinase activity can result in pathology if the effects are allowed to accumulate over a lifetime.”
To confirm whether similar enzymatic changes could be observed in human patients, the researchers also measured protein levels in the frontal cortex of human brains from deceased patients with AD and control individuals. Brains from AD patients showed a 20 percent increase in PKCα. Furthermore, phosphorylation of a known PKCα substrate was increased by approximately four-fold in these brains, further suggesting that PKCα activity was enhanced in the human AD brain.
“The PKCα M489V mutation has been a great way to test the role of this enzyme in AD, but there are many other ways to have aberrant PKCα,” said the author. “We’re finding that many mutations associated with AD are in genes that regulate PKCα, so a variety of gene variants may actually be converging onto this same important pathway.”
The authors note that several pharmacological inhibitors of PKCα have already been developed for use in cancer and could be repurposed to treat AD. Future drug development might focus on ways to selectively inhibit PKCα at the synapse.
“It’s increasingly clear that the amyloid plaques we see in AD are secondary to some other earlier process happening in the brain,” said the author. “Our findings add to a growing body of evidence that PKCα may be an important part of that process, and is a promising target for treating or preventing Alzheimer’s disease.”
https://www.nature.com/articles/s41467-022-34679-7
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fenhanced-activity-of&filter=22
Variant of protein kinase Cα drives cognitive decline in Alzheimer's
- 821 views
- Added
Latest News
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Other Top Stories
New pathway for accumulation of age-promoting 'zombie cells'
Read more
How EGF receptor sends signals into cells
Read more
Endogenous receptor surface mobility during synaptic plasticity and…
Read more
Recording gene expression order in DNA by CRISPR addition of retron…
Read more
Mechanisms and inhibition of Porcupine-mediated Wnt acylation
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Selenium, diabetes, and the…
By newseditor
Posted 23 Apr
Long-term neuropsychologica…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar