Choufani, C.; Fuggetta, N.; Sabbagh, B.; Moulin, C.; Franckhauser, C.; Lyonnais, S.; Perme, T.; Arteni, A.-A.; Pagnotta, S.; Rouquier, S.; Ruggieri, A.; Bousset, L.; Copic, A.

Perilipin 4 (PLIN4) belongs to the family of perilipins -- proteins that localize to lipid droplets (LDs). PLIN4 contains a giant (about 1000 aa) amphipathic helix, which folds on the LD surface and can substitute for phospholipids, thereby regulating LD surface tension. This region of PLIN4 is arranged in tandem repeats of 33 aa. Genetic expansion of this region is associated with skeletal muscle dysfunction in patients suffering from a late-onset vacuolar myopathy (MRUPAV). We demonstrate that purified fragments of the PLIN4 repetitive region form amyloid fibrils as characterized by cryo-EM and atomic force microscopy. The MRUPAV mutation drastically increases the kinetics of fibril formation and induces aggregation in budding yeast. The propensity to aggregate depends on the number of identical repeats and their sequence, and is strongly attenuated by the presence of lipid droplets, suggesting putative intervention strategies and an explanation for the observed tissue bias of the disease.