Mathews, P. | Search bioRxiv

bioRxiv2025

Amyloid-mediated RNA uptake by sperm for embryonic delivery

Seminal fluid RNA is essential for embryonic development, but the mechanism by which extracellular RNA is transferred from seminal fluid to sperm remains unclear. Here, we identify a role for functional amyloid fibrils in seminal fluid that bind and traffic RNA to mammalian sperm and, upon fertilization, the zygote. We show that highly cationic peptides in seminal fluid phase separate with RNA to form amyloid fibrils. Cryo-electron tomography reveals that these amyloid fibrils are internalized by sperm. Furthermore, biophysical and in vitro fertilization experiments show that amyloid-bound RNA reaches the zygote where molecular chaperones control release of RNA for translation. Our work uncovers a mechanism for RNA trafficking from seminal fluid to the zygote, establishing amyloid fibrils as potential tools for RNA delivery during fertilization.

biophysics↗

bioRxiv2019

Melanoma-secreted Amyloid Beta Supresses Neuroinflammation and Promotes Brain Metastasis

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. We performed unbiased proteomics analysis of melanoma short-term cultures, a novel model for the study of brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. This raised the exciting hypothesis that molecular pathways implicated in neurodegenerative disorders are critical for metastatic adaptation to the brain. Here, we show that melanoma cells require amyloid beta (A{beta}), a polypeptide heavily implicated in Alzheimers disease, for growth and survival in the brain parenchyma. Melanoma cells produce and secrete A{beta}, which activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that pharmacological inhibition of A{beta} decreases brain metastatic burden. Our results reveal a mechanistic connection between brain metastasis and Alzheimers disease - two previously unrelated pathologies, establish A{beta} as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma.

cancer biology↗