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

Marija Fjodorova,Anselme L Perrier,Morgane Louessard,Simon P Brooks,Zongze Li,Daniel C De La Fuente,Meng Li,Emma Dyke

doi:10.1016/j.stemcr.2019.07.015

Abstract

SummaryThe 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.

Highlights

Inhibitory g-amino butyric acid (GABA)-releasing medium spiny neurons (MSNs) are the principal projection neurons of the basal ganglia, receiving inputs from both glutamatergic cortical neurons and midbrain dopaminergic neurons
CTIP2 is a transcription factor expressed by all MSNs and is required for MSN development and transcriptional regulation of striatal genes (Arlotta et al, 2008; Onorati et al, 2014)
We show for the first time that deficits in protein kinase A (PKA)-dependent protein phosphorylation occur in human and mouse Huntington disease (HD) MSNs, potentially owing to CTIP2- and mutant huntingtin (mHTT)-co-regulated molecular signaling abnormalities as suggested by transcriptomic analysis

Summary

Introduction

Inhibitory g-amino butyric acid (GABA)-releasing medium spiny neurons (MSNs) are the principal projection neurons of the basal ganglia, receiving inputs from both glutamatergic cortical neurons and midbrain dopaminergic neurons. DARPP32 is a class-defining protein marker for striatal MSNs and a central mediator of dopaminergic and other first-messenger signaling in these cells. Phosphorylation of DARPP32 at threonine 34 (pDARPP32Thr34) by protein kinase A (PKA), following dopamine D1 receptor activation, is critically involved in regulating electrophysiological, transcriptional and behavioral responses of MSNs to physiological and pharmacological stimuli, including antidepressants, neuroleptics, and drugs of abuse (Yger and Girault, 2011). These findings point to an important role for PKA-regulated phosphorylation of DARPP32 in MSN health, with major implications for neurological disorders. CTIP2 protein levels are reduced in both human and rodent mutant huntingtin (mHTT)-expressing cells before the onset of MSN degeneration (Langfelder et al, 2016; Ring et al, 2015), pointing to a role for CTIP2 in Huntington disease (HD) pathogenesis

Results

Discussion

Conclusion