Journal Article

Modelling human neuronal catecholaminergic pigmentation in rodents recapitulates age-related neurodegenerative deficits

Romero-Giménez, Jordi, Vila, Miquel, Lorente-Picón, Marina, Nicolau, Alba, Parent, Annabelle, Bortolozzi, Analia, Liu, Jiong, Guillard-Sirieix, Camille, Peñuelas, Núria, Laguna, Ariadna, Giménez-Llort, Lydia, Pujol, Gemma, Fort, Patrice, Arthaud, Sébastien, Compte, Joan, Carballo-Carbajal, Iria, Miquel-Rio, Lluís, Cuadros, Thais, Gonzalez-Sepulveda, Marta, Xicoy, Helena

2024

Overview

One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models accurately mimicking the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside neurons that synthesize catecholamines. 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 common laboratory species, such as rodents, do not produce neuromelanin. Here we generate a tissue-specific transgenic mouse, termed tgNM, 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. We show that, 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 could help explore new research avenues in brain aging and neurodegeneration. Unlike humans, rodents do not accumulate the brain pigment neuromelanin in catecholamine neurons with age. The transgenic mouse model here presented accumulates neuromelanin and mimics the early physiopathology of Parkinson’s disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/51 / 14 / 14/19 / 631/378/1689/1718 / 631/378/2611 / 64 / 64/110 / Age composition / Aging / Aging - metabolism / Animal models / Animals / Bioaccumulation / Brain / Brain - metabolism / Brain - pathology / Catecholamine / Catecholamines / Catecholamines - metabolism / Degeneration / Disease Models, Animal / Female / Human health and pathology / Humanities and Social Sciences / Humans / Life Sciences / Male / Melanin / Melanins - metabolism / Mice / Mice, Inbred C57BL / Mice, Transgenic / Monophenol Monooxygenase - metabolism / Motor task performance / multidisciplinary / Neurobiology / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - genetics / Neurodegenerative Diseases - metabolism / Neurodegenerative Diseases - pathology / Neurons / Neurons - metabolism / Neurons and Cognition / Parkinson's disease / Pigmentation / Pigments / Rodents / Science / Science (multidisciplinary) / Tissues / Transgenic mice / Tyrosinase