Enzyme Trabid Explains Why Men Face Higher Neurodegeneration Risk

Men and women do not age the same way. Their brains degrade at different rates, and the diseases that come with age—Alzheimer's, Parkinson's—strike them with different force. Scientists have long observed this gap without fully understanding its source. A new study in fruit flies offers a molecular explanation: a single enzyme called Trabid, which controls how proteins are broken down and recycled inside brain cells, operates differently in males and females, and this difference appears to drive the sex-specific vulnerability to neurodegeneration.

The research centers on a cellular problem that accumulates over time. In aging brains, proteins misfold and clump together. Normally, cells have a cleanup system: proteins are tagged with a molecule called ubiquitin, which marks them for destruction. But when this tagging system goes wrong, damaged proteins pile up, triggering inflammation and eventually cell death. This process underlies both Alzheimer's and Parkinson's disease. What has remained unclear is why men face higher risk than women—why the same pathology produces different outcomes depending on sex.

Working with Drosophila melanogaster, the common fruit fly, researchers created flies with a mutated version of Trabid, the fly equivalent of a human enzyme called a deubiquitylase. Deubiquitylases do the opposite of the tagging system: they remove the ubiquitin markers from proteins, essentially deciding which proteins get destroyed and which survive. When Trabid was disabled in the flies, the researchers observed sex-specific effects. Both male and female flies showed problems—their movement deteriorated, their sleep patterns fractured—but males were hit harder. Male flies with the Trabid mutation experienced more severe loss of locomotion and died younger than females with the same mutation.

The mechanism turned out to involve two interconnected systems. First, when Trabid failed, the immune genes in the flies' brains became hyperactive, triggering excessive inflammation. When the researchers suppressed these immune genes specifically in the brain cells called glia—the immune cells of the nervous system—they could rescue the male flies' movement deficits and restore their lifespan. This suggested that males were more vulnerable to the inflammatory cascade triggered by Trabid loss. Second, the researchers identified a stress protein called Hsc70-4 that appeared to protect female flies but not males. This protein was a direct target of Trabid's enzymatic activity, meaning Trabid controlled how much Hsc70-4 accumulated in cells. In females, this protective protein seemed to buffer against the damage; in males, it did not.

The findings rest on detailed molecular analysis. The team examined the entire landscape of ubiquitinated proteins in fly brains—the ubiquitinome—and mapped how protein composition differed between sexes when Trabid was broken. They also performed biochemical experiments in test tubes to confirm that Trabid directly interacts with Hsc70-4. The picture that emerged is one of sex-specific regulation: the same enzyme controls protein degradation differently in males and females, leading to different outcomes when that enzyme fails.

What this means for human disease remains to be determined. Fruit flies have simpler brains than humans, and the leap from fly genetics to human medicine is never straightforward. But the finding points toward a concrete biological mechanism for sex dimorphism in neurodegeneration—a mechanism that could, in principle, be targeted with drugs. If Trabid's activity or the inflammatory response it controls could be modulated differently in men and women, it might be possible to slow or prevent age-related brain disease more effectively than current approaches allow. The research suggests that sex-specific treatments for Alzheimer's and Parkinson's are not merely a matter of adjusting dosages, but of addressing fundamentally different biological vulnerabilities.