Abstract Body

The twin discoveries by Dr. Oleh Hornykiecz of nigrostriatal dopamine deficiency in Parkinson disease (PD) and the amelioration of symptoms by L-DOPA administration represent milestone events in the history of medicine. What did Dr. Hornykiewicz wish to pass on to younger scientists? One of his frequently communicated conviction was that a disease of the human brain should be studied in human brain. Here, a former student demonstrates two examples of applying that legacy to research on the functions of two PD-linked genes: PRKN and SNCA. By studying >100 human brains, we discovered a novel function for parkin as an antioxidant. Parkin neutralizes reactive oxygen species and sequesters reactive electrophilic species (including dopamine quinone) through the function of the primate-specific residue C95. The sequestration effect may also contribute to neuromelanin formation [Tokarew et al., 2021]. In parallel work on olfactory epithelia studied in autopsy material and murine skulls, we discovered high expression levels of alpha-synuclein in olfactory sensory neurons, including the formation of proteinase K-resistant oligomers in their axons. These observations led to the identification of two functions of alpha-synuclein, namely in mammalian olfaction and antimicrobial defence against select RNA viruses [Tomlinson et al., 2017]. Ongoing research efforts focus on further validation of parkin's antioxidant role during dopamine metabolism and the characterization of alpha-synuclein misprocessing in olfactory neurons downstream of microbial encounters in the nasal cavity. These are aimed at better differentiating the pathogenesis of recessive PD versus late-onset, hyposmia-associated PD. The advice of Dr. Hornykiewicz to prioritize studies of the human brain in PD research continues to guide our field.