Objective: To gain an understanding of the underlying pathological mechanisms of Parkinson’s disease (PD)-related hyposmia using post-mortem human olfactory bulbs and an in vivo model of PD.

Background: Hyposmia is an early, canonical symptom that precedes the characteristic motor dysfunctions of PD. Despite the high prevalence of hyposmia, the neurobiology of dysfunction is poorly understood, hampering its utility as an aid to early diagnosis.

Method: Human and mouse olfactory bulb tissue were analyzed using a combination of Western blot, ELISA, HPLC, ICP-MS, and IHC techniques. In vivo, olfaction was analyzed using odour detection test, and dopamine was modulated pharmacologically using intraperitoneal cocaine and haloperidol.

Results: Our characterization of human PD olfactory bulbs has demonstrated alterations in dopamine metabolism. There is an increase in the expression of tyrosine hydroxylase (TH), despite this not translating into an increase in dopamine. Simultaneously, there are significantly reduced levels of homovanillic acid, suggesting a failure of dopamine breakdown by catechol-O-methyltransferase (COMT). There is a compensatory increase in COMT protein levels, however, this COMT has reduced activity, possibly due to significant reductions in S-adenosylmethionine. Furthermore, metal analysis has implicated a potential role of environmental factors, indicated by an increase in the level of lead and zinc. With an increase in dopamine and metals, unsurprisingly there is an indication of an oxidative stress environment, supported by increases in DJ-1 and calcium.
We have previously shown that the tau KO mice have pre-motor hyposmia [1], hence we used them as a model to understand the consequence of dopaminergic changes in the olfactory system. Expanding on these findings here we show that the tau KO mice show features of dopamine mis-metabolism synonymous with the human tissue, without an increase in the overall level of dopamine. Furthermore, the hyposmia present in these animals can be rescued using the D₂R antagonist Haloperidol, and hyposmia can be induced in healthy mice using cocaine and Haloperidol, further supporting our hypothesis that dopamine modulation can directly affect olfaction.

Conclusion: Taken together the studies suggest that hyposmia in PD may be driven by the failure of dopamine metabolism and increased D₂R activation in the olfactory bulb.

References: [1] Beauchamp LC, Chan J, Hung LW, et al. Ablation of tau causes an olfactory deficit in a murine model of Parkinson’s disease. Acta neuropathologica communications 2018;6(1):57.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-dopamine-mis-metabolism-in-preclinical-parkinsons-disease-olfactory-deficits/