Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington’s Disease PSC-Derived Striatal Neurons

Lange, Jenny and Wood-Kaczmar, Alison and Ali, Aneesa and Farag, Sahar and Ghosh, Rhia and Parker, Jennifer and Casey, Caroline and Uno, Yumiko and Kunugi, Akiyoshi and Ferretti, Patrizia and Andre, Ralph and Tabrizi, Sarah J. (2021) Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington’s Disease PSC-Derived Striatal Neurons. Frontiers in Cellular Neuroscience, 15. ISSN 1662-5102

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Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT-targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein.

Item Type: Article
Subjects: Science Global Plos > Medical Science
Depositing User: Unnamed user with email support@science.globalplos.com
Date Deposited: 12 Apr 2023 08:09
Last Modified: 15 Sep 2023 04:13
URI: http://ebooks.manu2sent.com/id/eprint/558

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