TY - JOUR
T1 - Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function
AU - Longo, Francesco
AU - Mancini, Maria
AU - Ibraheem, Pierre L.
AU - Aryal, Sameer
AU - Mesini, Caterina
AU - Patel, Jyoti C.
AU - Penhos, Elena
AU - Rahman, Nazia
AU - Mamcarz, Maggie
AU - Santini, Emanuela
AU - Rice, Margaret E.
AU - Klann, Eric
N1 - Funding Information:
Acknowledgements We thank Dr Caroline Bass (University at Buffalo) for providing the AAV2/10-TH-iCre and AAV2/10-TH-dsRED adeno-associated viruses and Dr Randal Kaufman (Sanford Burnham Prebys Medical Discovery Institute) for providing the Eif2(S51A) mouse line; We wish to acknowledge Claudia Farb for exceptional technical assistance and Dr Prerana Shrestha for critical advice and review of this paper. We thank all members of the Klann laboratory for critical feedback and discussions. The MATLAB script for Vmax analysis was written and provided by Dr Charles Nicholson at NYU Grossman School of Medicine. This study was supported by National Institutes of Health Grants NS034007 and NS047384 (EK), DA038616 (MER), U.S. Department of Defense Award W81XWH-15-1-0360 (EK), and the Marlene and Paolo Fresco Institute for Parkinson’s Disease and Movement Disorders (MM and MER).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/11
Y1 - 2021/11
N2 - Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2α kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2α signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2α signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and motor phenotypes. Conditional expression of phospho-mutant eIF2α in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2α phosphorylation for these phenotypes. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as changes in axonal DA release and uptake in the striatum that mirror the pattern of motor changes observed. Taken together, our findings show that proper regulation of PERK-eIF2α signaling in DA neurons is required for normal cognitive and motor function in a non-pathological state, and also provide new insight concerning the onset of neuropsychiatric disorders that accompany UPR failure.
AB - Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2α kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2α signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2α signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and motor phenotypes. Conditional expression of phospho-mutant eIF2α in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2α phosphorylation for these phenotypes. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as changes in axonal DA release and uptake in the striatum that mirror the pattern of motor changes observed. Taken together, our findings show that proper regulation of PERK-eIF2α signaling in DA neurons is required for normal cognitive and motor function in a non-pathological state, and also provide new insight concerning the onset of neuropsychiatric disorders that accompany UPR failure.
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U2 - 10.1038/s41380-021-01099-w
DO - 10.1038/s41380-021-01099-w
M3 - Article
C2 - 33879865
AN - SCOPUS:85105101439
SN - 1359-4184
VL - 26
SP - 6427
EP - 6450
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 11
ER -