CTIP2-Regulated Reduction in PKA-Dependent DARPP32 Phosphorylation in Human Medium Spiny Neurons: Implications for Huntington Disease

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. •CTIP2 protects human MSNs against oxidative stress-induced cell death•PKA-regulated DARPP32 and GLUR1 phosphorylation is reduced in CTIP2-deficient MSNs•HD MSNs share CTIP2-dependent downregulation of protein phosphorylation by PKA In this article, Fjodorova and colleagues provide mechanistic and potential therapeutic insight into striatal neurodegeneration caused by CTIP2 hypofunction. CTIP2 plays an essential role in human MSN homeostasis via regulating PKA-dependent DARPP32 phosphorylation and protecting MSNs from oxidative stress-induced cell death. Protein phosphorylation deficits occur in human and mouse Huntington disease MSNs due to CTIP2- and mHTT-co-regulated molecular signaling abnormalities.