Alzheimer-Linked Protein Fibers Discovered Delivering Cargo Inside Sperm Cells
Unexpectedly, protein fibers typically associated with neurodegenerative disorders like Alzheimer’s and Parkinson’s disease have been found playing a vital biological role in semen, where they shepherd genetic material directly into sperm cells. Researchers at Columbia’s Zuckerman Institute published these findings in the research journal Molecular Cell, raising the possibility that these amyloid proteins could eventually help improve gene-editing technologies such as CRISPR.
From HIV Research to Seminal Discovery
The unusual project originated from investigations into the virus HIV. Previous research established that amyloid fibrils present in semen could assist HIV in entering cells within the reproductive tract. William Mallen, PhD, the study’s lead author, who was a doctoral student in the Fitzpatrick lab at the time, wondered if those same fibrils might help natural bodily materials enter sperm—specifically RNA, the genetic molecule that translates DNA instructions into protein molecules. While seminal fluid contains abundant small RNAs known to influence gene activity in developing embryos, the mechanism of how this RNA crosses into sperm remained an open mystery.
Researchers noted that amyloids are positively charged while RNA carries a negative charge. Opposites attract like magnets, prompting Dr. Mallen to use fluorescent labels to test if the molecules bind together. The experiments confirmed they do, suggesting the durable amyloid scaffold protects fragile RNA molecules from harsh conditions. Subsequent analysis using cryo-electron tomography—a high-powered microscopy technique that fires electron beams at frozen specimens to produce near-atomic-resolution 3D images—allowed scientists to confirm that gold-labeled amyloid proteins actually penetrated inside sperm cells rather than merely embedding on their surfaces.
Amyloids Enhance RNA Entry into Sperm
Using a fluorescent protein to measure the rate of entry, the team found that amyloids significantly enhanced how fast RNA entered the sperm. Once inside, another protein called clusterin assisted in separating the RNA from the amyloid structure. Anthony Fitzpatrick, PhD, principal investigator at Columbia’s Zuckerman Institute and senior author on the paper, described the findings as a seminal discovery
and credited Dr. Mallen as a fearless graduate student willing to pursue real swing-for-the-fences type of science.
Dr. Mallen observed that at the Fitzpatrick lab, everything is ‘go big or go home.’
While the exact function of the amyloid-shuttled RNA once inside the sperm remains under investigation, earlier studies indicate that seminal RNA can trigger epigenetic modifications, switching genes on or off in offspring and potentially passing down metabolic disorders like insulin resistance through paternal lines in mice. Experiments demonstrated that amyloids could transport RNA molecules large enough to encode a green fluorescent protein. Embryos fertilized with this treated sperm generated at least ten times more of that protein than sperm exposed to RNA alone. Because current CRISPR applications frequently rely on modified viruses that can trigger immune responses, researchers suggest that human-based amyloid fibrils could offer a safer delivery mechanism for therapeutic genes.
