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Hum Mol Genet. 2018 Aug 15;27(16):2863-2873. doi: 10.1093/hmg/ddy200.

PAK1 regulates ATXN1 levels providing an opportunity to modify its toxicity in spinocerebellar ataxia type 1.

Bondar VV1,2, Adamski CJ1,2,3, Onur TS1,2, Tan Q1,2, Wang L1,2, Diaz-Garcia J1,2, Park J1,2, Orr HT4,5, Botas J1,2,6, Zoghbi HY1,2,3,6,7.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
2
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
3
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, USA.
4
Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA.
5
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
6
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
7
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is caused by the expansion of a trinucleotide repeat that encodes a polyglutamine tract in ataxin-1 (ATXN1). The expanded polyglutamine in ATXN1 increases the protein's stability and results in its accumulation and toxicity. Previous studies have demonstrated that decreasing ATXN1 levels ameliorates SCA1 phenotypes and pathology in mouse models. We rationalized that reducing ATXN1 levels through pharmacological inhibition of its modulators could provide a therapeutic avenue for SCA1. Here, through a forward genetic screen in Drosophila we identified, p21-activated kinase 3 (Pak3) as a modulator of ATXN1 levels. Loss-of-function of fly Pak3 or Pak1, whose mammalian homologs belong to Group I of PAK proteins, reduces ATXN1 levels, and accordingly, improves disease pathology in a Drosophila model of SCA1. Knockdown of PAK1 potently reduces ATXN1 levels in mammalian cells independent of the well-characterized S776 phosphorylation site (known to stabilize ATXN1) thus revealing a novel molecular pathway that regulates ATXN1 levels. Furthermore, pharmacological inhibition of PAKs decreases ATXN1 levels in a mouse model of SCA1. To explore the potential of using PAK inhibitors in combination therapy, we combined the pharmacological inhibition of PAK with MSK1, a previously identified modulator of ATXN1, and examined their effects on ATXN1 levels. We found that inhibition of both pathways results in an additive decrease in ATXN1 levels. Together, this study identifies PAK signaling as a distinct molecular pathway that regulates ATXN1 levels and presents a promising opportunity to pursue for developing potential therapeutics for SCA1.

PMID:
29860311
PMCID:
PMC6077814
DOI:
10.1093/hmg/ddy200
[Indexed for MEDLINE]
Free PMC Article

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