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ABSTRACT 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. Access through your institution Buy or subscribe This is a

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PERRY SYNDROME-ASSOCIATED P150GLUED IN MIDBRAIN DOPAMINERGIC NEURONS LEADS TO PROGRESSIVE NEURODEGENERATION AND ENDOPLASMIC RETICULUM ABNORMALITIES Article Open access 07 March 2023 LOSS OF

DJ-1 FUNCTION CONTRIBUTES TO PARKINSON’S DISEASE PATHOGENESIS IN MICE _VIA_ RACK1-MEDIATED PKC ACTIVATION AND MAO-B UPREGULATION Article 25 May 2023 IMPAIRED STRIATAL GLUTATHIONE–ASCORBATE

METABOLISM INDUCES TRANSIENT DOPAMINE INCREASE AND MOTOR DYSFUNCTION Article Open access 28 October 2024 DATA AVAILABILITY The data that support the findings of this study are available from

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PubMed  Google Scholar  Download references 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). AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Center for Neural Science, New York University, New York, NY, USA Francesco Longo, Pierre L. Ibraheem, Sameer Aryal, Caterina Mesini, Maggie Mamcarz, Emanuela

Santini & Eric Klann * Department Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA Maria Mancini & Margaret E. Rice * Sackler Institute of Graduate Biomedical

Sciences, NYU School of Medicine, New York, NY, USA Sameer Aryal * Department of Neurosurgery, NYU School of Medicine, New York, NY, USA Jyoti C. Patel, Elena Penhos, Nazia Rahman & 

Margaret E. Rice * NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA Jyoti C. Patel, Elena Penhos, Nazia Rahman, Margaret E. Rice & Eric

Klann * Department of Neuroscience, Biomedicum, Karolinska Institute, Stockholm, Sweden Emanuela Santini Authors * Francesco Longo View author publications You can also search for this

author inPubMed Google Scholar * Maria Mancini View author publications You can also search for this author inPubMed Google Scholar * Pierre L. Ibraheem View author publications You can also

search for this author inPubMed Google Scholar * Sameer Aryal View author publications You can also search for this author inPubMed Google Scholar * Caterina Mesini View author publications

You can also search for this author inPubMed Google Scholar * Jyoti C. Patel View author publications You can also search for this author inPubMed Google Scholar * Elena Penhos View author

publications You can also search for this author inPubMed Google Scholar * Nazia Rahman View author publications You can also search for this author inPubMed Google Scholar * Maggie Mamcarz

View author publications You can also search for this author inPubMed Google Scholar * Emanuela Santini View author publications You can also search for this author inPubMed Google Scholar *

Margaret E. Rice View author publications You can also search for this author inPubMed Google Scholar * Eric Klann View author publications You can also search for this author inPubMed 

Google Scholar CONTRIBUTIONS FL carried out the behavioral experiments, performed slice electrophysiology experiments, and collected and analyzed all in vivo and ex vivo data. MM carried out

and analyzed the FSCV experiments. SA carried out western blotting and collected ex vivo data. PLI and CM carried out behavioral experiments and collected in vivo and ex vivo data. JCP

performed DAT-mediated dopamine uptake analysis. MER coordinated, performed, and analyzed HPLC experiments. EP and NR carried out HPLC experiments. MD performed genotyping of the mice. FL,

EK, ES conceived the studies. MM and MER participated in the design of the studies. FL and EK designed and coordinated all experiments and wrote the paper. All authors read and commented on

the paper. CORRESPONDING AUTHOR Correspondence to Eric Klann. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Longo, F., Mancini, M., Ibraheem, P.L. _et al._ Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons

alters motor and cognitive function. _Mol Psychiatry_ 26, 6427–6450 (2021). https://doi.org/10.1038/s41380-021-01099-w Download citation * Received: 08 October 2020 * Revised: 20 March 2021

* Accepted: 01 April 2021 * Published: 20 April 2021 * Issue Date: November 2021 * DOI: https://doi.org/10.1038/s41380-021-01099-w SHARE THIS ARTICLE Anyone you share the following link with

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