Nuclear Pore Pathology in Triple A Syndrome Matthew J Elrick1 and Jeffrey D Rothstein1 1Johns Hopkins School of Medicine, Department of Neurology
The nuclear pore complex is a macromolecular structure residing in the nuclear envelope of all eukaryotic cells, where it forms the sole conduit for nucleocytoplasmic transport. Recent studies have demonstrated dysfunctional nucleocytoplasmic transport and mislocalization of nucleoporins as a critical event in several neurodegenerative disorders, including amyotrophic lateral sclerosis1-3 and Huntington disease.4 However, the mechanistic link between nuclear pore pathology and neurodegeneration remains unknown. Triple A syndrome is a pediatric onset neurodegenerative disorder due to autosomal recessive mutation in the AAAS gene, which encodes the nucleoporin ALADIN.5,6 By studying a disorder whose most proximal cause is disruption of the nuclear pore, we aim to better understand the downstream events ultimately leading to neurodegeneration. This approach avoids the confounding presence of additional upstream and off-target pathologies present in most neurodegenerative disorders. Here, we present the characterization of nuclear pore pathology in cell culture models of Triple A syndrome, including mislocalization of Nups and alteration of protein trafficking through the nuclear pore.
1 Freibaum, B. D. et al.Nature 525, 129-133, (2015). 2 Jovicic, A. et al.Nat Neurosci 18, 1226-1229, (2015). 3 Zhang, K. et al.Nature 525, 56-61, (2015). 4 Grima, J. C. et al.Neuron 94, 93-107 e106, (2017). 5 Brooks, B. P. et al.Clin Genet 68, 215-221, (2005). 6 Cronshaw, J. M. & Matunis, M. J. Proc Natl Acad Sci U S A 100, 5823-5827, (2003).
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