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

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.

Significance statement: Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases worldwide. Because therapies that cure or even prevent their progression are lacking, research is focused on the identifying earliest signs of disease as targets for diagnosis and treatment. The locus coeruleus (LC), the main source of the neurotransmitter n norepinephrine (NE) in the brain, is one of the first brain regions affected in both AD and PD. LC dysregulation promotes prodromal AD and PD symptoms, while its degeneration accelerates disease progression. Here we identify neuromelanin (NM) pigment as a LC vulnerability factor that induces neuronal hyperactivity followed by cell death. Approaches that mitigate NM accumulation and toxicity may target the earliest phases of neurodegenerative disease.