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Publications

Journal Article Preprint Epublish 18 citations

PubMed: 36945637 DOI: 10.1101/2023.03.07.530845

Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus.

bioRxiv

Authors: Alexa F Iannitelli, Leslie Hassanein, Margaret M Tish, Bernard Mulvey, Harris E Blankenship, Anu Korukonda, L Cameron Liles, Amanda L Sharpe, Jean-Francoise Pare, Rosa Villalba, Arielle Segal, Steven A Sloan, Keri Martinowich, Joseph D Dougherty, Katharine E McCann, Yoland Smith, Michael J Beckstead, David Weinshenker

Affiliations

  • Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • Department of Psychiatry, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA.
  • Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
  • Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, 73117.
  • Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
  • Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA.

Abstract

The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is among the earliest site of pathology in both Alzheimer's disease (AD) and Parkinson's disease (PD), and it undergoes catastrophic degeneration later in both disorders. Dysregulation of the LC is thought to contribute to prodromal symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC loss promotes cognitive decline. However, the mechanisms responsible for its selective vulnerability are unknown. It has been suggested that neuromelanin (NM) pigment contributes to LC susceptibility, but causal relationships have been difficult to test because rodents do not naturally produce NM. Here, we report that viral-mediated expression of human tyrosinase induced pigmentation in mouse LC neurons that recapitulated key features of natural primate NM. One week of NM accumulation resulted in LC neuron hyperactivity, reduced tissue NE levels, transcriptional changes, and anxiety-like behavior. By 6-10 weeks, NM accumulation was associated with severe LC neuron neurodegeneration and microglial engulfment of the pigment granules, while the anxiety-like behavior abated. These phenotypes are reminiscent of LC dysfunction and cell death in AD and PD, validating this model for studying the consequences of NM accumulation in the LC as it relates to neurodegenerative disease.

MeSH

Pathology, Neurons, Phenotype, Locus Coeruleus, Melanins, Monophenol Monooxygenase