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

Neuron. 2018 Jun 27;98(6):1155-1169.e6. doi: 10.1016/j.neuron.2018.05.022. Epub 2018 Jun 7.

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.

Keywords: Drosophila; ER-mitochondrial contact site; Parkinson’s disease; circadian rhythm; hypothalamic neuron; iPS cells; neuropeptidergic neuron; non-motor symptoms; phophatidylserine; sleep.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Drosophila Proteins / genetics
  • Drosophila melanogaster
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Hypothalamus / metabolism*
  • Induced Pluripotent Stem Cells
  • Lipid Metabolism*
  • Mitochondria / metabolism
  • Neurons / metabolism*
  • Neuropeptides / metabolism
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology*
  • Phosphatidylserines / metabolism*
  • Phosphatidylserines / pharmacology
  • Protein-Serine-Threonine Kinases / genetics
  • Sleep Disorders, Circadian Rhythm / genetics
  • Sleep Disorders, Circadian Rhythm / metabolism
  • Sleep Disorders, Circadian Rhythm / physiopathology*
  • Sleep* / drug effects
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitination

Substances

  • Drosophila Proteins
  • Neuropeptides
  • Phosphatidylserines
  • Ubiquitin-Protein Ligases
  • PINK1 protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • park protein, Drosophila