UAB Researchers Uncover Key to Rare Muscle Disease

Researchers at the Universitat Autònoma de Barcelona (UAB) have made a significant discovery in the field of Limb-girdle muscular dystrophy type 3 (LGMD D3), a rare disease that causes progressive muscle weakness. The disease was previously believed to be caused by point mutations in the hnRNPDL-2 protein, a little-known protein that can assemble to form functional amyloid structures. However, the UAB research team has determined the structure of the amyloid fibers formed by the protein and found that the inability to form these structures is actually what causes the disease.

The researchers used high-resolution cryo-electron microscopy (cryo-EM) to determine the structure of the amyloid fibers, which is a first for a Spanish research team. The structure of the protein differs from other pathological amyloid proteins in that it has a highly hydrophilic nucleus, and amyloid formation is necessary for the protein's function. 

The results challenge previous assumptions about the origin of the disease and how it should be treated. The researchers now propose that molecules that stabilize the protein's structure or facilitate its formation would be the most appropriate therapy.

In recent years, the structures of various amyloid fibers formed by fragments of RNPs have been solved, but these assemblies may not necessarily coincide with those adopted in the context of complete proteins.

To resolve the structure of hnRNPDL-2, the research team applied special techniques to resolve amyloid structures, utilizing the power of cryo-EM to study the function of RNPs and their link to disease.

The discovery highlights the importance of understanding the molecular structures of amyloids, which can undergo both functional and pathological aggregation, to determine their distinctive qualities and functions. This new technology at the UAB will allow researchers to study the fibrillary states of other functional amyloids and the effect of mutations to better understand their implications in health and disease.

The results of the UAB study can potentially change the way LGMD D3 is treated and understood, with the researchers now looking to expand their work to better understand the implications of functional amyloids in health and disease.

Their discovery highlights the power of cryo-EM to study these little-known proteins, which are associated with diseases such as Alzheimer's, muscular dystrophies, cancer, and neurodevelopmental and neuropsychiatric disorders.