| Popis: |
Myofibrillar myopathies (MFMs) are a group of muscle diseases exhibiting progressive muscle weakness, and are characterised at the cellular level by structural failure of the muscle, and the formation of cytoplasmic protein aggregates. There is an immense amount of variation in the clinical features presented including the age of onset, which ranges from infancy to late adulthood; the selective involvement of cardiac and respiratory muscle groups; and severity covering the full spectrum from mild muscle weakness to premature lethality. Mutations in eight genes have been implicated in myofibrillar myopathy (MFM), all of which encode for proteins localised to the Z-disk of the sarcomere. The remarkable consistency in pathology between all MFMs suggests a common mechanism of disease, which is currently unknown. Therefore, to identify this common mechanism I generated zebrafish models of filamin C (FLNC) and BCL2-related athanogene 3 (BAG3)-related MFM. I overexpressed fluorescently tagged, full-length, MFM causing mutant FLNC and BAG3, and showed that the presence of either mutant protein results in protein aggregation, which is the first hallmark feature of MFM. Loss of either of the two proteins on the other hand, leads to contraction dependent fibre failure at the Z-disk. Remarkably, the MFM causing mutant proteins were capable of rescuing the loss of function fiber failure phenotype dismissing a role of haploinsufficiency in MFM. I demonstrate instead that aggregates include not only the mutant protein but also result in the sequestration of wildtype protein, and other proteins required for muscle integrity. The sequestration eventually leads to insufficient protein being available in the muscle therefore resulting in fibre failure and muscle weakness. My studies therefore describe how dominant mutations in FLNC and BAG3 result in muscle failure and, provide an explanation for the delayed onset and progressive nature of the disease. A key revelation from my studies is the role of toxic aggregates in triggering muscle weakness. I demonstrate that stimulation of the autophagic protein degradation pathway can reduce the number of cells affected by aggregates. I have therefore not only determined the mechanism of disease in MFM but also provided a promising avenue for the development of therapies, and suitable animal models in which to evaluate them. |
