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An integrative evolutionary medicine approach identifies factors that prevent pathological protein aggregation in an ALS-linked protein

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness, paralysis, and eventual respiratory failure. One of the genes associated with ALS is the fused in sarcoma (FUS) gene, which codes for the FUS protein. Mutations in the prion-like domain of the FUS protein have been implicated in the development of ALS. The prion-like domain facilitates protein aggregation and the formation of toxic protein aggregates, leading to neuronal dysfunction and cell death.

To better understand ALS and the role of FUS mutations that can lead to disease pathogenesis, we took a bioinformatic and evolutionary approach through a collaborative effort between our research institute and the laboratory of Prof. Eugene Shakhnovich at Harvard University.  Our findings, recently published in the journal PNAS (Proceedings of the National Academy of Sciences), have shed light on one of the most perplexing questions surrounding FUS and similar aggregating-prone proteins: How do these proteins form functional liquid-like condensates within cells without transitioning into the harmful amyloid aggregates associated with disease?

In our research, we uncovered a key mechanism: post-translational phosphorylation. This process acts as a crucial "handle" that prevents the transition of intracellular FUS condensates from liquid to solid, thereby avoiding the formation of amyloids. Through molecular simulations, we studied hundreds of proteins including 85 diverse mammalian FUS sequences, and examined the impact of phosphorylation sites and their spatial arrangement on amyloid prevention. Remarkably, our work confirmed that phosphorylation significantly reduces the β-sheet propensity in amyloid-prone regions of FUS. Moreover, our comprehensive evolutionary analysis revealed a fascinating pattern. Mammalian FUS prion-like domains (PLDs) contain an increased prevalence of amyloid-prone sequences compared to neutrally evolved control sequences. This suggests that mammalian FUS proteins have evolved to favor self-assembly, utilizing these amyloid-prone regions for efficient phase separation. However, mammalian sequences also have evolutionarily selected phosphosites near these amyloid-prone regions, acting as checkpoints to prevent liquid-solid transitions and safeguard the integrity of the condensates.

Our research not only provides crucial insights into the pathogenesis of ALS but also underscores the power of combining bioinformatics, computational biophysics, and evolutionary analysis to unravel the molecular basis of genetic diseases. Understanding the precise impact of changes in phosphorylation on disease development can pave the way for the development of innovative therapeutic strategies. We enthusiastically invite researchers from both academia and industry who would like to collaborate with us in further exploring this exciting field of research. Please contact Dr. Pouria Dasmeh, who heads the “computational and evolutionary medicine” research group for further details.

Souce: https://www.pnas.org/doi/10.1073/pnas.2215828120

Funded through BMBF