**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Guglielmo Verona, University College London, London, United Kingdom; University of Pavia, Department of Molecular Medicine

**Main Body of the Abstract**
The mechanism that converts native human transthyretin into amyloid fibrils in vivo is still unclear and debated. The fibrillogenesis of globular proteins in in vitro models is commonly achieved using non-physiological conditions of pH, temperature or organic solvents. Transthyretin amyloid formation can instead be achieved under physiological conditions through a mechano-enzymatic mechanism involving specific serine proteases such as trypsin or plasmin. We studied S52P and L111M transthyretin variants, both causing a severe form of systemic amyloidosis mostly targeting the heart at a relatively young age with heterogeneous phenotype among patients. Our investigation of thermodynamics show that both proteins are significantly destabilized when compared to other amyloidogenic variants. However, despite showing a similar thermodynamic stability, the L111M variant seems to have enhanced susceptibility to cleavage and a lower tendency to form fibrils than S52P in the presence of specific proteases and biomechanical forces. Heparin strongly enhances the aggregation propensity of L111M transthyretin, but has no to minimal effect on the S52P variant. Similarly, fibrillar seeds  affect the fibrillogenesis of both proteins, with a stronger effect on the L111M variant. According to our model of mechano‑enzymatic fibrillogenesis, both full-length and truncated monomers, released after the first cleavage, can enter into fibrillogenesis or degradation pathways. Our findings show that the kinetics of the two processes can be affected by several factors, such as intrinsic amyloidogenicity due to the specific mutations, environmental factors including heparin and fibrillar seeds that significantly accelerate the fibrillogenic pathway.



**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Guglielmo Verona, University College London, London, United Kingdom; University of Pavia, Department of Molecular Medicine

**Main Body of the Abstract**
The mechanism that converts native human transthyretin into amyloid fibrils _in vivo_ is still unclear and debated. The fibrillogenesis of globular proteins in _in vitro_ models is commonly achieved using non-physiological conditions of pH, temperature or organic solvents. Transthyretin amyloid formation can instead be achieved under physiological conditions through a mechano-enzymatic mechanism involving specific serine proteases such as trypsin or plasmin. We studied S52P and L111M transthyretin variants, both causing a severe form of systemic amyloidosis mostly targeting the heart at a relatively young age with heterogeneous phenotype among patients. Our investigation of thermodynamics show that both proteins are significantly destabilized when compared to other amyloidogenic variants. However, despite showing a similar thermodynamic stability, the L111M variant seems to have enhanced susceptibility to cleavage and a lower tendency to form fibrils than S52P in the presence of specific proteases and biomechanical forces. Heparin strongly enhances the aggregation propensity of L111M transthyretin, but has no to minimal effect on the S52P variant. Similarly, fibrillar seeds  affect the fibrillogenesis of both proteins, with a stronger effect on the L111M variant. According to our model of mechano‑enzymatic fibrillogenesis, both full-length and truncated monomers, released after the first cleavage, can enter into fibrillogenesis or degradation pathways. Our findings show that the kinetics of the two processes can be affected by several factors, such as intrinsic amyloidogenicity due to the specific mutations, environmental factors including heparin and fibrillar seeds that significantly accelerate the fibrillogenic pathway.



Degradation versus fibrillogenesis, two alternative pathways modulated by seeds and glycosaminoglycans PB17 (#481)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.