Methods of Treating Diseases Associated with Polyalanine Expansion Mutations

The invention describes the inhibition of ubiquitin like modifier activating enzyme 6 (UBA6) by disease-causing polyalanine expanded mutant proteins in a variety of cell types. Polyalanine-expanded proteins can interact with UBA6 and inhibit UBA6-mediated protein degradation of downstream targets, such as the neurodevelopmental E3-ubiquitin ligase E6-AP. Ectopic administration of vectors expressing UBA6 in patient cells with polyalanine-expanded proteins attenuates the disease phenotypes.   


At least nine rare diseases are caused by expansion mutations of polyalanine tracts in different nuclear proteins, which give rise to congenital neurological phenotypes. The vast majority of cases are sporadic and de novo in-frame duplications have been reported. Currently there is not treatment that can slow down or prevent disease phenotypes.  


A method of treating a subject having a disease associated with a polyalanine expansion mutation, the method comprising administering to the subject a therapeutically effective amount of an agent capable of upregulating expression or activity of UBA6 in nervous system cells of the subject, thereby treating the subject.


A therapeutically effective amount of an agent, such as either a DNA sequence or a RNA sequence administered to patients with polyalanine expansion mutations.


The method was tested in mouse primary neurons, non-neuronal human cell lines and induced pluripotent stem cells (iPSC)-derived neurons from patients with polyalanine expansion mutations.

PCT has been filed.


Amer-Sarsour, F., Falik, D., Berdichevsky, Y., Kordonsky, A., Prag, G., Vatine, G. D. and Ashkenazi, A. (2022) Polyalanine disease mutations impair UBA6-dependent ubiquitination. Preprint in bioRxive. doi: https://doi.org/10.1101/2022.0… 

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