The deposition of misfolded proteins is a defining feature of many age-dependent human diseases, including the increasingly prevalent neurodegenerative diseases. Why this happens is unclear. Cells normally strive to ensure that proteins are correctly folded by using powerful and sophisticated mechanisms to maintain protein homeostasis under adverse conditions. However, with age, the cellular defence systems against misfolded proteins seem to gradually fail, leading to the accumulation of misfolded proteins, with devastating consequences for cells and organisms. Therefore, improving the cells’ ability to deal with misfolded proteins could be useful to reduce and prevent neurodegenerative diseases.
Research led by Anne Bertolotti, in the LMB’s Neurobiology Division, has identified a novel, selective and safe pharmacological approach to boost a natural cellular defense against misfolded proteins and thus safely preventing protein misfolding diseases in mice.
Using cultured cells and mice as a model organism, Anne’s group have found a small molecule, named Sephin1 (a selective inhibitor of a holophosphatase) which selectively binds and inhibits PPP1R15A, a regulatory subunit of the protein phosphatase PP1, to safely prolong the benefit of a phospho-signaling pathway and prevent the motor, histological and molecular defects of two, otherwise unrelated diseases in mice, Charcot-Marie-Tooth 1B and amyotrophic lateral sclerosis. This small molecule boosts the natural cellular defence systems against damaged proteins and prevents them from accumulating and becoming harmful.
This demonstrates that selective inhibition of PPP1R15A can safely prevent two neurodegenerative diseases caused by the misfolding of proteins in mice. It also establishes that phosphatases, up to now thought of as unsuitable drug targets, are targetable, opening up a broad range of possibilities to manipulate cellular functions for potential therapeutic benefits.
This research could be a first step towards developing drugs to prevent neurodegenerative diseases.
This work was funded by the MRC, the European Research Council, EMBO, the Human Frontier Science Program, the Swiss National Science Foundation, the Italian Ministry of Health and NIH.