CTIP2-regulated reduction in PKA-dependent DARPP32 phosphorylation in human medium spiny neurons: implications for Huntington’s disease

Fjodorova, Marija, Louessard, Morgane, Li, Zongze ORCID: https://orcid.org/0000-0002-4803-4643, De La Fuente, Daniel, Dyke, Emma, Brooks, Simon ORCID: https://orcid.org/0000-0001-9853-6177, Perrier, Anselme and Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643 2019. CTIP2-regulated reduction in PKA-dependent DARPP32 phosphorylation in human medium spiny neurons: implications for Huntington’s disease. Stem Cell Reports 13 (3-6) , pp. 448-457. 10.1016/j.stemcr.2019.07.015

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Abstract

The mechanisms underlying the selective degeneration of medium spiny neurons (MSNs) in Huntington disease (HD) remain largely unknown. CTIP2, a transcription factor expressed by all MSNs, is implicated in HD pathogenesis because of its interactions with mutant huntingtin. Here, we report a key role for CTIP2 in protein phosphorylation via governing protein kinase A (PKA) signaling in human striatal neurons. Transcriptomic analysis of CTIP2-deficient MSNs implicates CTIP2 target genes at the heart of cAMP-Ca2+ signal integration in the PKA pathway. These findings are further supported by experimental evidence of a substantial reduction in phosphorylation of DARPP32 and GLUR1, two PKA targets in CTIP2-deficient MSNs. Moreover, we show that CTIP2-dependent dysregulation of protein phosphorylation is shared by HD hPSC-derived MSNs and striatal tissues of two HD mouse models. This study therefore establishes an essential role for CTIP2 in human MSN homeostasis and provides mechanistic and potential therapeutic insight into striatal neurodegeneration.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Biosciences Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Publisher:	Elsevier
ISSN:	2213-6711
Funders:	Medical Research Council
Date of First Compliant Deposit:	29 July 2019
Date of Acceptance:	22 July 2019
Last Modified:	26 Jul 2024 16:23
URI:	https://orca.cardiff.ac.uk/id/eprint/124505

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