ER Lipid Defects in Neuropeptidergic Neurons Impair Sleep Patterns in Parkinson's Disease

Jorge S. Valadas, Giovanni Esposito, Dirk Vandekerkhove, Katarzyna Miskiewicz, Liesbeth Deaulmerie, Susanna Raitano, Philip Seibler, Christine Klein, Patrik Verstreken*

*Korrespondierende/r Autor/-in für diese Arbeit
7 Zitate (Scopus)

Abstract

Parkinson's disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts. These excessive contact sites cause abnormal lipid trafficking that depletes phosphatidylserine from the endoplasmic reticulum (ER) and disrupts the production of neuropeptide-containing vesicles. Feeding mutant animals phosphatidylserine rescues neuropeptidergic vesicle production and acutely restores normal sleep patterns in mutant animals. Hence, sleep patterns and circadian disturbances in Parkinson's disease models are explained by excessive ER-mitochondrial contacts, and blocking their formation or increasing phosphatidylserine levels rescues the defects in vivo. Valadas et al. show that ER lipid imbalance causes sleep pattern defects in Parkinson's disease by preventing the formation of secretory vesicles required for the release of the neuropeptides. Restoring the ER lipid balance by supplementation with phosphatidylserine rescues the cellular and behavioral defects.

OriginalspracheEnglisch
ZeitschriftNeuron
Jahrgang98
Ausgabenummer6
Seiten (von - bis)1155-1169
Seitenumfang15
ISSN0896-6273
DOIs
PublikationsstatusVeröffentlicht - 27.06.2018

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  • Querschnittsbereich: Medizinische Genetik

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