Protein fingered in rare psychosis

Doctors have long known that fasting exacerbates porphyria, an inherited disease marked by psychotic episodes. They’ve also known that glucose infusions, which induce insulin secretion, can mitigate the attacks.

Researchers report in the Aug. 26 Cell that a protein called PGC-1-alpha is the linchpin connecting fasting, glucose, and insulin with porphyria episodes.

Porphyria probably caused the madness of King George III (SN: 8/6/05, p. 94: Available to subscribers at King George III should have sued). In people with this condition, mutated enzymes lead to the manufacture of defective heme, an essential iron compound found in many proteins. Instead of having healthy heme, porphyria patients accumulate toxic versions, bringing on sporadic attacks of psychosis.

To sort out the effect of fasting, biochemist Bruce M. Spiegelman of Harvard Medical School and the Dana-Farber Cancer Center in Boston and his colleagues chemically induced porphyria in mice. Some of the animals were also genetically engineered to lack PGC-1-alpha, which, when present, boosts the production of heme, normal or not.

The scientists found that mice with porphyria but lacking PGC-1-alpha didn’t have attacks when fasting, suggesting that the animals had stopped accumulating defective heme, Spiegelman says. The finding suggests that inhibiting PGC-1-alpha might ward off porphyria attacks in people.