Kavli Affiliate: Keri Martinowich
| Authors: Leslie Hassanein, Bernard Mulvey, Harris Blankenship, Margaret M Tish, Anu Korukonda, L Cameron Liles, Amanda L Sharpe, Jean-Francois Pare, Rosa Villalba, Xiangchuan Chen, Khan Hekmatyar, Jenny Yang, Daniel Huddleston, Seong Su Kang, Arielle Segal, Steven A Sloan, Keri Martinowich, Keqiang Ye, Joseph D Dougherty, Katharine E McCann, Yoland Smith, Michael J Beckstead, David Weinshenker and Alexa F Iannitelli
| Summary:
The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is among the first sites 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 early behavioral symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC loss promotes cognitive decline. However, the mechanisms responsible for this selective vulnerability are unknown. It has been suggested that neuromelanin (NM) pigment contributes to LC susceptibility, but a causal relationship has been difficult to test because rodents do not naturally produce NM. Here, we report that viral-mediated expression of human tyrosinase-induced pigmentation in male and female mouse LC neurons recapitulated key macroscopic and ultrastructural 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 weeks, NM accumulation was associated with severe cell-autonomous LC neuron degeneration, neuroinflammation, 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 diseases.