Age-dependent neuromelanin accumulation in a novel humanized transgenic mouse model for Parkinson's disease and brain aging

Abstract

Trabajo presentado en Neuroscience, celebrado en Chicago (Estados Unidos), del 19 al 23 de octubre de 2019Parkinson's disease (PD) is characterized by a selective and progressive loss of neurons that contain the dark brown pigment neuromelanin (NM), especially neurons from the substantia nigra (SN) and the locus coeruleus (LC), as well as, to a lesser extent, neurons from the ventral tegmental area (VTA) and the dorsal motor nucleus of the vagus nerve (DMNV). In humans, NM accumulates with age, the latter being the main risk factor for PD. The contribution of NM to PD pathogenesis remained unknown because, unlike humans, common laboratory animals lack NM. To overcome this major limitation, we have recently generated a new humanized rodent model based on the overexpression of human tyrosinase in the SN (AAV-hTyr). These animals show an age-dependent production of human-like NM, up to levels reached in elderly humans, and an age-dependent parkinsonian phenotype. We have now generated a humanized transgenic mouse model (Tg-TH-hTyr) that represents the first model that recapitulates the age-dependent accumulation and distribution of NM in all catecholaminergic neuronal cell groups in the brain, including SN, VTA, LC, and DNV. Using this unique animal model, we have assessed the functional, morphological and molecular implications of progressive NM accumulation in cellular functions. Our results show that NM accumulation affects neuronal function and viability in different catecholaminergic neuronal groups, which is relevant to PD pathogenesis and to the manifestation of both motor and non-motor symptoms of the disease