Publicaciones científicas

E46K alpha-synuclein pathological mutation causes cell-autonomous toxicity without altering protein turnover or aggregation

26-sep-2017 | Revista: Proceedings of the National Academy of Sciences of USA

Ignacio Íñigo-Marco  1   2 , Miguel Valencia  1   3   4 , Laura Larrea  1 , Ricardo Bugallo  1   2 , Mikel Martínez-Goikoetxea  5 , Iker Zuriguel  5 , Montserrat Arrasate  6   3   4


α-Synuclein (aSyn) is the main driver of neurodegenerative diseases known as "synucleinopathies," but the mechanisms underlying this toxicity remain poorly understood.

To investigate aSyn toxic mechanisms, we have developed a primary neuronal model in which a longitudinal survival analysis can be performed by following the overexpression of fluorescently tagged WT or pathologically mutant aSyn constructs.

Most aSyn mutations linked to neurodegenerative disease hindered neuronal survival in this model; of these mutations, the E46K mutation proved to be the most toxic. While E46K induced robust PLK2-dependent aSyn phosphorylation at serine 129, inhibiting this phosphorylation did not alleviate aSyn toxicity, strongly suggesting that this pathological hallmark of synucleinopathies is an epiphenomenon.

Optical pulse-chase experiments with Dendra2-tagged aSyn versions indicated that the E46K mutation does not alter aSyn protein turnover. Moreover, since the mutation did not promote overt aSyn aggregation, we conclude that E46K toxicity was driven by soluble species.

Finally, we developed an assay to assess whether neurons expressing E46K aSyn affect the survival of neighboring control neurons. Although we identified a minor non-cell-autonomous component spatially restricted to proximal neurons, most E46K aSyn toxicity was cell autonomous.

Thus, we have been able to recapitulate the toxicity of soluble aSyn species at a stage preceding aggregation, detecting non-cell-autonomous toxicity and evaluating how some of the main aSyn hallmarks are related to neuronal survival.

CITA DEL ARTÍCULO  Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):E8274-E8283.  doi: 10.1073/pnas.1703420114. Epub 2017 Sep 12.