Kavli Affiliate: Keri Martinowich
| Authors: Alexa F Iannitelli, Leslie Hassanein, Bernard Mulvey, Harris Blankenship, L Cameron Liles, Amanda L Sharpe, Jean-Francois Pare, Arielle Segal, Steven A Sloan, Keri Martinowich, Katharine E McCann, Joseph D Dougherty, Yoland Smith, Michael J Beckstead and David Weinshenker
| Summary:
The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is an early site of pathology in both Alzheimers disease (AD) and Parkinsons 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-NE loss promotes cognitive decline. However, the mechanisms responsible for its selective vulnerability are unknown. The LC is among the only structures in the brain that produces appreciable amounts of neuromelanin (NM), a dark cytoplasmic pigment. It has been proposed that NM initially plays a protective role by sequestering toxic catecholamine metabolites and heavy metals, but may become harmful during aging as it overwhelms cellular machinery and is released during neurodegeneration. Rodents do not naturally produce NM, limiting the study of causal relationships between NM and LC pathology. Adapting a viral-mediated approach for expression of human tyrosinase, the enzyme responsible for peripheral melanin production, we successfully promoted pigmentation in mouse LC neurons that recapitulates key ultrastructural features of endogenous NM found in primates. Pigment expression results in LC neuron hyperactivity, reduced tissue NE levels, transcriptional changes, and novelty-induced anxiety phenotypes as early as 1-week post-injection. By 6-10 weeks, NM accumulation is associated with severe LC neuron neurodegeneration and microglial engulfment of the pigment granules, while the anxiety-like behavior is abated. These phenotypes are reminiscent of LC dysfunction and cell death in AD and PD, validating this model for studying the consequences of pigment accumulation in the LC as it relates to neurodegenerative disease.