Biology subjects

Cornwall, G. A.

Publications and source records attributed to Cornwall, G. A..

6 recordsLinked to original sources

bioRxiv2026

Amyloid/RNA Condensates with Germ Granule Characteristics Are Present in Rat Epididymal Spermatozoa and Exhibit Prion-Like Propagation Activity

Environmental exposures to the germline can alter its epigenome resulting in new traits being acquired by offspring. While the epigenetic carrier in mammalian spermatozoa remains unknown, studies in C.elegans show that amyloids and sperm-specific populations of germ granules, phase-separated biomolecular condensates enriched in RNA-binding proteins and small noncoding RNAs, transmit heritable epigenetic phenotypes to descendant cells. Here we discovered that rat epididymal spermatozoa contain germ granule-like condensates in the head perforatorium, a cytoplasmic derived structure that participates in early post-fertilization events. The perforatoria condensates contain evolutionarily conserved germ granule markers and small noncoding RNAs and are enriched in amyloid, including those of the clinically relevant amyloidogenic proteins androgen receptor (AR) and TDP43. Further, perforatoria extracts exhibit prion-like propagation behavior by functioning as molecular seeds to template amyloid assembly in recombinant AR and TDP43. We propose that nature has conserved sperm germ granule-like structures throughout evolution to allow an organism to respond and adapt to a changed environment by passing environmentally encoded information to the embryo via a non-Mendelian protein-based mechanism of inheritance.

cell biology↗

bioRxiv2026

Altered Brain Extracellular Matrix Structure and Sex-Specific Learning/Memory Dysfunction in Mice Lacking the Functional Amyloid Cystatin-Related Epididymal Spermatogenic (CRES)

Cystatin-related epididymal spermatogenic (CRES) is a member of a reproductive subgroup of family 2 cystatins and part of a functional amyloid-containing extracellular matrix (ECM) with host defense functions in the epididymal lumen. CRES and the endogenous epididymal amyloid matrix exhibit high plasticity, forming distinct amyloid structures, with antimicrobial functions tailored to specific bacterial strains. We recently demonstrated that CRES/CRES amyloid is also present in the mammalian brain ECM. In this study, we utilized a CRES knockout (KO) mouse model to determine if the loss of CRES altered the structure of the hippocampal and cortical ECM and impacted brain function. We report that CRES KO male and female mice exhibited sex-specific structural changes in both the loose/interstitial and perineuronal net (PNN) ECM. Additionally, young CRES KO males but not females displayed deficits in learning, memory and executive functioning when compared to WT controls. In contrast, older CRES KO males did not exhibit behavioral deficits, a finding that correlated with the observation of a similar PNN ECM structure when compared to WT mice. Our data suggest that CRES functions as a regulatory or structural component of the brain ECM, contributing to its sex-specific structural organization and plasticity, affecting sex-specific behaviors of learning and memory.

neuroscience↗

bioRxiv2025

DNA modulates structural transitions and oligomerization kinetics of the functional amyloid CRES

Functional amyloids play critical roles in diverse physiological processes; however, the molecular mechanisms regulating their assembly remain unknown. The mouse epididymal lumen contains a functional amyloid- and nucleic acid-rich extracellular matrix with roles in host defense and sperm maturation. Cystatin-related epididymal spermatogenic (CRES), a reproductive cystatin and key component of the mammalian epididymal amyloid matrix, assembles into structurally heterogeneous amyloid forms to support the various roles of this extracellular matrix. Here, we show that CRES binds double-stranded DNA with sub-micromolar affinity in a sequence independent manner and that DNA binding accelerates amyloid formation by increasing local protein concentration and promoting specific oligomerization pathways. Using NMR spectroscopy, site-directed mutagenesis, and biophysical analyses, we find that DNA interacts primarily with the CRES loop region, thereby occluding one assembly mechanism and redirecting oligomerization through a pathway involving the L1 loop. These DNA-mediated changes in assembly kinetics and pathway selection suggest a regulatory mechanism for achieving structural and functional diversity in non-pathological amyloid systems. Our findings provide a molecular framework for understanding nucleic acid-guided amyloidogenesis and highlight how functional amyloids may exploit multiple assembly routes to fulfill their physiological roles.

biophysics↗

bioRxiv2025

The Functional Epididymal Amyloid Cystatin-Related Epididymal Spermatogenic (CRES) is a Component of the Mammalian Brain Extracellular Matrix

CRES is the defining member of a reproductive subgroup of family 2 cystatins of cysteine protease inhibitors. We previously showed that CRES and other subgroup members are part of a highly plastic amyloid-containing extracellular matrix (ECM) with host defense functions in the mouse epididymal lumen. Based on parallels between the epididymis and the brain, we hypothesized that CRES and CRES amyloids might also function within the brain including the ECM. Here we show that CRES is produced by hippocampal neurons and astrocytes in the male and female mouse and human brain. Further, approximately 50% of hippocampal astrocytes from aged mice, like the aged human donor samples, had significantly reduced levels of CRES compared to younger mice, suggesting an age-related decline in CRES could contribute to altered brain function. Immunofluorescence experiments showed CRES colocalized with the ECM markers phosphacan and wisteria floribunda agglutinin indicating that CRES is part of the ECM. CRES monomer and high molecular weight SDS-resistant forms were found in insoluble fractions of the hippocampus, cortex, cerebellum, and midbrain and bound to the protein aggregation disease (PAD) ligand, which preferentially binds amyloids but not protein monomers, suggesting a population of CRES exists in the brain as an amyloid structure. Collectively, our studies demonstrate that CRES/CRES amyloid is present in the mammalian brain and may contribute to ECM structure and function. Significance StatementWe previously established that the cystatin-related epididymal spermatogenic (CRES) protein is part of an amyloid-containing extracellular matrix (ECM) that protects the male germline in the epididymal lumen. Here we demonstrate that CRES is present within the mouse and human brain. Using cell biological and biochemical approaches, we show that CRES is found in hippocampal astrocytes and specific neuronal populations, including those that possess perineuronal nets, and colocalized with ECM markers suggesting it is part of the ECM. Biochemical analyses suggested a population of CRES is present as an ordered amyloid structure. Our studies reveal CRES is present in the male and female mammalian brain and may contribute to brain structure and function as a biological amyloid. Keyword: hippocampus, mouse, human, plasticity

neuroscience↗

bioRxiv2023

The Mouse Epididymal Amyloid Matrix: A Mammalian Counterpart of a Bacterial Biofilm

The mouse epididymis is a long tubule connecting the testis to the vas deferens. Its primary functions are to mature spermatozoa into motile and fertile cells and to protect them from pathogens that ascend the male tract. We previously demonstrated that a functional extracellular amyloid matrix surrounds spermatozoa in the epididymal lumen and has host defense functions; properties not unlike that of an extracellular biofilm that surrounds and protects a bacterial community. Here we show the epididymal amyloid matrix also structurally resembles a biofilm by containing eDNA, eRNA, and mucin-like polysaccharides. Further these structural components exhibit comparable behaviors and perform functions like their counterparts in bacterial biofilms. Our studies suggest that nature has used the ancient building blocks of bacterial biofilms to form an analogous structure that nurtures and protects the mammalian male germline.

cell biology↗

bioRxiv2023

Pathogenic Mutations in the C2A Domain of Dysferlin form Amyloid that Activates the Inflammasome.

Limb-Girdle Muscular Dystrophy Type-2B/2R is caused by mutations in the dysferlin gene (DYSF). This disease has two known pathogenic missense mutations that occur within dysferlins C2A domain, namely C2AW52R and C2AV67D. Yet, the etiological rationale to explain the disease linkage for these two mutations is still unclear. In this study, we have presented evidence from biophysical, computational, and immunological experiments which suggest that these missense mutations interfere with dysferlins ability to repair cells. The failure of C2AW52R and C2AV67D to initiate membrane repair arises from their propensity to form stable amyloid. The misfolding of the C2A domain caused by either mutation exposes {beta}-strands, which are predicted to nucleate classical amyloid structures. When dysferlin C2A amyloid is formed, it triggers the NLRP3 inflammasome, leading to the secretion of inflammatory cytokines, including IL-1{beta}. The present study suggests that the muscle dysfunction and inflammation evident in Limb-Girdle Muscular Dystrophy types-2B/2R, specifically in cases involving C2AW52R and C2AV67D, as well as other C2 domain mutations with considerable hydrophobic core involvement, may be attributed to this mechanism.

biophysics↗