Gabriele Zaffagnini

FMNS | Institute for Genetics (UoC)

Dr. Gabriele Zaffagnini CECAD Cologne
Dr. Gabriele Zaffagnini

Principal Investigator

Research Areas

2
3

Proteostasis in Female Reproductive Aging

Female fertility strongly decreases with age, primarily due to reduced oocyte quality. We are interested in how proteostasis preserves oocyte quality and how its dysregulation affects reproductive aging.

Research Focus

Oocytes are the female germ cells, which develop into fertilizable eggs. In most mammals, oocytes are formed only before birth and are used for the entire fertile life of the individual. In other words,each of us derives from an oocyte that was as old as our mom at the time of our conception.This means up to several decades!

How do oocytes maintain protein homeostasis during such a long time? How does proteostasis decay contributes to reduced oocyte quality with age?

Even though they can wait for decades before being fertilized, oocytes are not eternal. Starting on average in the fourth decade of their life, women experience a decay in their fertility, mostly due to decreased quality of their oocytes. This phenomenon is called “reproductive aging”. Reproductive aging is becoming a growingly urgent societal problem, as in many European Countries women are increasingly delaying maternity. However, the causes of reduced oocyte quality with advanced maternal age are still largely unknown.

We are interested in the mechanisms that allow mammalian oocytes to remain healthy for decades, and in the causes of their eventual demise during reproductive aging. For this, we primarily focus on protein homeostasis. Protein homeostasis (proteostasis) is essential in all cell types. Long-lived cells such as neurons are particularly sensitive to proteostasis decay during aging, and defective proteostasis is associated with several age-related diseases, such as neurodegeneration.

Each of us derives from an oocyte that was as old as our mom at the time of our conception. How did this oocyte maintain protein homeostasis for so many years?

Our Goals

Our main goal is to understand how proteostasis is maintained in mammalian oocytes during their extended lifespan, and how its dysregulation influences reproductive aging.

We have recently discovered that mouse oocytes store protein aggregates in large non-membrane-bound compartments, that we have named EndoLysosomal Vesicular Assemblies (ELVAs) (Zaffagnini et al., 2024). ELVAs harbor all the major degradative systems in the cell, including endolysomes, autophagosomes, and proteasomes, embedded in a liquid-like matrix. Inactive in immature oocytes, ELVAs activate degradation shortly before fertilization, thereby disposing of the stored aggregates. Forced inheritance of aggregates in the embryo impairs embryonic development, indicating that ELVAs play a fundamental role in maintaining oocyte quality to ensure reproduction.

Our current research focuses on how ELVAs are assembled, regulated, and eventually dissolved during early embryonic development. For this, we take an interdisciplinary approach, combining biochemistry, live oocyte imaging, and -omics to understand how ELVAs function. We are mainly interested in three research lines:

  • ELVA regulation during oocyte maturation and aging.
    ELVAs relocate to the oocyte cortex and activate degradation upon oocyte maturation. How are these processes regulated? How is reproductive aging influencing ELVA activity.
     
  • Endolysosomal trafficking in a liquid-like matrix
    Efficient vesicle trafficking is essential during endocytosis and autophagy to achieve cargo degradation. In ELVAs, endolysosomal vesicles are embedded in a liquid-like matrix, inside which they must fuse with each other to achieve degradation of the stored aggregates. How is endolysosomal trafficking regulated inside ELVAs?
     
  • ELVA dissolution and lysosomal exocytosis
    ELVAs disappear during the first embryonic division, followed by a peak of lysosomal exocytosis. Blockade of lysosomal exocytosis in mouse embryos leads to developmental arrest, indicating that this process is required for physiological embryonic development. How is lysosomal exocytosis coupled to ELVA dissolution? What is its role during development?

Key Publications


  1. Zaffagnini et al., 2024. Mouse oocytes sequester aggregated proteins in degradative super-organelles. Cell. 2024 Feb 29;187(5):1109-1126.e21. doi: 10.1016/j.cell.2024.01.031. 
Dr. Gabriele Zaffagnini CECAD Cologne
Dr. Gabriele Zaffagnini

Principal Investigator

Research Areas

2
3