Amyotrophic lateral sclerosis (ALS) is a terrible debilitating neurodegenerative disease involving the motor neurons – the nerve cells that transport a command generated in the brain to the muscles. This degeneration results in rapidly progressing muscle weakness, atrophy, muscle spasms, spasticity, difficulty in moving, and even swallowing, speaking and breathing, eventually leading to death.
Approximately 10% of ALS cases are hereditary and involve mutations in one of ca. 20 genes so far identified. PFN1 is one of such genes, coding for the protein named profilin-1, and in 2012 was found to be associated with familial ALS. Eight mutations of profilin-1 have been identified (see figure below), although two of them are likely to be benign or represent moderate risk factors rather than disease causing mutations.
Eight mutations of profilin1-1 © Fabrizio Chiti/De Gruyter
In this study, published in Biological Chemistry, and previous papers, researchers purified and studied seven of the eight profilin-1 mutants and investigated their conformational stability, structural features and aggregation behaviour in vitro. The mutations were found to increase the tendency of the protein to misfold (i.e. to adopt a structure different from the native one) and aggregate into abnormal inclusion bodies.
A statistical analysis of the data indicates significant correlations between aggregation propensity and structural perturbations of the native state, indicating that the mechanism by which the mutations are pathogenic is based on their ability to perturb the structure of the native protein.
This implies that mutations representing benign or moderate risk factors cause only limited structural perturbations of the native protein, that pathogenic mutations cause substantial alterations, whereas the highly aggressive mutations cause the most severe structural destabilisation.
In this scenario pathogenic mutations of profilin-1 make it difficult for the protein to remain in a native soluble state because of its misfolding and eventually its aggregation, which causes problems at the molecular and cytological levels that eventually lead to ALS.
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