Merdanovic, M. | bioRxiv Science

bioRxiv2024

A non-autonomous protein quality control mechanism targeting tau aggregate propagation

Tauopathies such as Alzheimers disease, frontotemporal dementia with Parkinsonism, and other neurodegenerative disorders are characterized by the spread of tau pathology from an initial brain region to neuroanatomically connected areas. At the molecular level, spreading involves aggregation of tau in a donor cell, externalization of transmissible fragments of amyloid fibrils, internalization by an acceptor cell, followed by seeded aggregation of endogenous tau. However, the protein quality control mechanisms that counteract tau aggregation, and in particular its spreading process, are not well understood. In this context, a co-migrating factor performing location-independent interference of fibril formation and transmission would be an appropriate conceptual solution. Here, we show that the cell-to-cell transfer of the widely conserved serine protease HTRA1 impedes tau pathology by targeting multiple steps within the spreading process. Our results suggest a defense mechanism against the intercellular spread of pathogenic protein conformations.

biochemistry↗

bioRxiv2024

A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils

AL amyloidosis is one of the most common types of systemic amyloidosis, caused by the deposition in tissues of fibrillar aggregates of abnormal immunoglobulin (Ig) light chain (LC), leading to organ dysfunction. The most frequent and severe forms affect the kidneys and heart, the latter being associated with a poor prognosis. Despite extensive efforts to decipher the mechanisms of fibril formation and their toxicity, the lack of reliable in vivo models hinders the study of the disease in its physiological context. We developped a transgenic mouse model producing high amounts of a human AL light chain (LC). While mice exceptionnaly develop spontaneous AL amyloidosis and do not exhibit organ toxicity due to the circulating amyloidogenic free LC, a single injection of amyloid fibrils, made up of the variable domain (VL) of the human LC, or soluble VL led to amyloid deposits in the heart, vessels, spleen and, to a lesser extent, in the kidney and other visceral tissues. AL fibrils in mice contain both full length and fragmented LC with a fragmentation pattern highly superposable to that of human AL fibrils from the same LC subgroup (IGLV6-57). They also develop an early cardiac dysfunction closely resembling the human disease with increased NT-proBNP,and activation of pathways involved in the extracellular matrix remodeling and fibrosis. Overall, this transgenic AL model closely reproduces human cardiac AL amyloidosis and shares with humans the biochemical composition of the deposits, arguing for a conserved mechanism of amyloid fibrils formation. It also shows that a partial degradation of the LC is likely required to initiate amyloid fibril formations. This model offers a new avenue for research on AL amyloidosis and fills an important gap for the preclinical evaluation of new therapies.

pathology↗