Using a viral hTyr rat model to induce neuromelanin, the study shows that NM accumulation alters nigral dopamine neuron survival, intrinsic firing and mitochondrial function with higher NM levels in males and sex-biased motor and non-motor (anxiety) phenotypes.

By linking neuromelanin buildup to mitochondrial dysfunction and sex-specific vulnerability in a manipulable preclinical model, the work offers a mechanistic target and platform for developing sex-tailored neuroprotective strategies and biomarkers for Parkinson's disease.

Neuromelanin (NM) is a dark pigment that accumulates with age in human substantia nigra pars compacta (SNpc) dopamine (DA) neurons, conferring the dark look that inspired nigral area's name. Although NM has long been associated with Parkinson's disease (PD), as melanized neurons favorably degenerate during disease development, NM functions within SNpc DA neurons are still mostly elusive. Here, using an NM-producing rat model generated by viral vector-induced expression of human tyrosinase (hTyr), we inspected NM impact on survival and activity of nigral DA neurons, nigral mitochondrial functionality, and behaviors resembling non-motor and motor PD symptoms. Our data reveal sex differences in NM effects on the nigrostriatal dopamine circuit and PD-like behaviors. We found higher NM levels in nigral DA neurons of males and down-regulation of nigral tyrosine hydroxylase (TH) irrespective of sex, as well as sex-biased alterations in neuronal firing activity and underlying intrinsic currents of nigral DA neurons, nigral mitochondrial functions, and non-motor PD symptoms (anxiety). In conclusion, this study discloses novel NM effects within nigral DA neurons, advancing our comprehension of sex-specific features shaping sex-biased vulnerability to PD.