Updated project metadata. Neuromelanin is a black-brownish pigment, present in so-called neuromelanin granules (NMG) in the cell bodies of dopaminergic neurons in the substantia nigra. These neurons are lost in neurodegenerative diseases like Parkinson’s disease and dementia with Lewy bodies (DLB). Although it is known that lipids, proteins, and environmental toxins accumulate in NMG, the function of NMG in health and disease remains elusive, as well as the synthesis of neuromelanin. We therefore isolated NMG and surrounding SN tissue from control and DLB patients by laser micro-dissection and analyzed the proteomic profile by tandem-mass spectrometry. The NMG core proteome consisted of several proteins specific for stress granules regardless of health status, indicating a potential, yet unknown, association of NMG and stress granules. Potential-disease related proteomic alterations lead us to the hypothesis of an eventual impairment of the lipid metabolism, as associated proteins were lower abundant in SN tissue of DLB patients. Furthermore, α-synuclein was found to be specifically higher abundant in NMG of DLB patients. As α-synuclein is known to form neurotoxic aggregates, the accumulation inside of NMG suggests a neuroprotective role of NMG in synucleinopathies. With our results, we are able to propose alternative hypotheses on NMG origin and function.