Skip to main content
Premium Trial:

Request an Annual Quote

Late-Onset Alzheimer's Disease Linked to Rare Variants in Kinase Gene

NEW YORK (GenomeWeb) – Researchers from the University of California, San Diego, and elsewhere have linked gain-of-function variants within the PRKCA gene to late-onset Alzheimer's disease.

In their search for genes linked to the disease, the researchers focused on the multi-isozyme protein kinase C (PKC) family, as many of its members have previously been implicated in Alzheimer's. As they reported today in Science Signaling, the researchers screened nearly 1,350 people from 410 late-onset Alzheimer's disease (LOAD) families, and uncovered three rare PRKCA variants in five families — all in afflicted members. These rare variants appeared to increase PKCa catalytic activity, they added.

PKC has also been implicated in cancer, the researchers noted. At first, scientists thought that PKC helped cancer cells survive, and PKC inhibitors were tested as cancer drugs, but co-senior author Alexandra Newton at the UCSD School of Medicine noted that it's actually been found to be the opposite: PKC slows cell growth.

"PKC serves as the brakes to cell growth and survival, so cancer cells benefit when PKC is inactivated. Now, our latest study reveals that too much PKC activity is also bad, driving neurodegeneration," Newton said in a statement. "This means that drugs that failed in clinical trials for cancer may provide a new therapeutic opportunity for Alzheimer's disease."

In a series of cell- and mouse-based studies, she and her colleagues first found that PKCα is necessary for amyloid-β plaques, one of the hallmarks of Alzheimer's disease, to affect synaptic transmission. In particular, they reported that mice lacking the PKCα gene had neurons that worked as they should, even in the presence of Aβ. But when the PKCα gene was added back in, Aβ could again impair neuronal function, suggesting that PKCα is needed for Aβ to have its adverse effects.

To gauge whether PKCα has a role in human Alzheimer's disease, the researchers looked for rare variants in PRKCA, the gene that encodes PKCα, in whole-genome sequencing data obtained from 410 families as part of the National Institute of Mental Health's Alzheimer's Disease Genetics Initiative.

From this, they identified three rare variants: M489V, V636I, and R324W. These variants were not present in unaffected family member, suggesting that they co-segregate with LOAD patients.

These rare disease-linked variants lead to increased cellular activity, Newton and her colleagues found. Two of them — M489V and V636I — affect key regulatory segments of the PKC family — segments that interface with the Ca2+-sensing C2 domain, which keeps PKCα in an autoinhibited conformation. The variants may affect its ability to stay in that autoinhibited shape as, for instance, the M489V variant exchanges a bulky methionine for a smaller valine.

The third variant, R324W, could also affect autoinhibition as that change occurs at a hinge that connects a kinase domain to a regulatory moiety.

In cell assays, the researchers found that these variants did lead to an increased rate of dephosphorylation of PKCα and increased agonist-driven PKCα function, as compared to wild-type cells.

"Thus, PKCα is required for deleterious synaptic effects of Aβ, observed early in LOAD, and increased PKCα activity can contribute to human LOAD," Newton and her colleagues wrote in their paper.

This also suggests that PKC inhibitors, such as the ones that had been tested as cancer drugs might be repurposed to stave off the effects of Aβ on synapses and, perhaps, lessen the loss of cognitive function, the researchers said. At the same time, they added that PKCα mutations could also be used to gauge disease susceptibility.