Modelling human brain-wide pigmentation in rodents recapitulates age-related multisystem neurodegenerative deficits

SUMMARY One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models that accurately mimic the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside catecholaminergic neurons. Neurons reaching the highest neuromelanin levels preferentially degenerate in Parkinson’s, Alzheimer’s and apparently healthy aging individuals. However, this brain pigment is not taken into consideration in current animal models because, in contrast to humans, common laboratory species such as rodents do not produce neuromelanin. Here we generated a tissue-specific transgenic mouse that mimics the human age-dependent brain-wide distribution of neuromelanin within catecholaminergic regions, based on the constitutive catecholamine-specific expression of human melanin-producing enzyme tyrosinase. In parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model may open new research avenues in the field of brain aging and neurodegeneration.