Canales, C. | Search bioRxiv

bioRxiv2026

When longevity becomes chemistry: Why rodent brains lack neuromelanin

Background: The biology of neuromelanin (NMel) is linked to Parkinson's disease, in which pigment accumulation and release contribute to dopaminergic cell loss. Rodent brains lack detectable levels of NMel, despite possessing the molecular machinery required for its synthesis. The basis for this absence remains unknown. Objectives: To determine whether long-living rodents accumulate NMel and to test whether lifespan constraints explain the lack of pigmentation in mice and rats. Methods: Histological stains were conducted in brain samples of mole rats of different ages to disclose the potential pigmentation of catecholaminergic centers and to determine the chemical phenotype of pigmented neurons. Results: Mole rats exhibited clear age-dependent NMel accumulation beginning after two years of age, with the highest pigmentation levels observed in neurons of the locus coeruleus. Conclusions: Accumulation of NMel is a slow kinetic process that requires extended longevity. Common laboratory rodents lack pigmented brains simply because they do not live long enough to reach detectable NMel levels.

neuroscience↗

bioRxiv2026

Tier-specific location of Lewy body pathology and related neuromelanin levels drive dopaminergic cell vulnerability in pigmented non-human primates

Although a differential vulnerability of dopaminergic neurons to degeneration based on their specific location within the dorsal and ventral tiers of the substantia nigra pars compacta (SNcD and SNcV, respectively) has long been postulated, the underlying mechanisms sustaining these tier-specific differences remain poorly understood. Here, upon inducing a viral-mediated enhancement of neuromelanin (NMel) accumulation within dopaminergic neurons in non-human primates, the distribution of Lewy body-like inclusions (LBs) was analyzed within identified SNcD and SNcV neurons, together with their intracellular NMel levels. Results showed that the vast majority of intracytoplasmic inclusions were found in SNcV neurons, and indeed correlated to higher pigmentation levels. By contrast, only very few LBs were found in calbindin-positive neurons of the SNcD, which in parallel exhibited very low levels of NMel accumulation. These results postulate an additive effect made of a tier-specific location of LB burden together with high pigmentation levels as synergistic drivers sustaining the preferential vulnerability of SNcV dopaminergic neurons. Moreover, the evidence obtained here supported that NMel accumulation beyond a given threshold triggers the aggregation of endogenous -Syn in the form of LBs; therefore, approaches intended to reduce pigmentation levels in SNcV neurons would likely induce a neuroprotective effect by preventing the subsequent aggregation of -Syn.

neuroscience↗