Prodromal Parkinson’s disease, DOPAL and the olfactory bulb: from an organotypic model to clinical relevance

Parkinson’s disease (PD) is an untreatable neurodegenerative disorder affecting more than six million people worldwide, a figure expected to more than double within a generation. The causes of PD are still largely unknown and, at present, no cure is able to halt the progression of the disease, with the available treatments offering merely symptomatic relief. A main limitation in the development of new therapies is the lack of relevant models, especially those mimicking the prodromal stage of the disease. Particularly affected in this phase is the olfactory bulb (OB), the brain region responsible for the initial processing of olfactory sensory information. OB pathology is observed in patients both at a functional and molecular level, with olfactory dysfunction being a prominent feature of prodromal PD and accompanied by the aggregation of α-synuclein, another hallmark of the disease, in olfactory regions. In order to provide a testing platform for the development of disease-modifying therapies, a novel prodromal model of olfactory pathology was successfully developed using both organotypic and primary OB cultures. The use of ex vivo organotypic slices combines the advantages of an in vitro system, such as easy experimental access, simplicity and reduced costs and time, without the loss of the complex milieu and three dimensional architecture of the in vivo tissue. To induce parkinsonian features, cultures were exposed to 3,4- dihydroxyphenylacetylaldehyde (DOPAL), a metabolite of dopamine, that, according to the “catecholaldehyde hypothesis” is thought to play a central role in PD pathogenesis. As DOPAL accumulation has been detected in post-mortem parkinsonian brains and is present in the OB, the use of this metabolite makes our models more physiologically relevant than those based on other toxins, such as hydroxydopamine. Exposure of cultured olfactory bulb slices to DOPAL is able to recapitulate many aspects of PD pathology. In particular, increased oxidative stress, mitochondrial dysfunction, neurodegeneration and protein aggregation are measurable impacts. Moreover, the toxic metabolite induces transcriptomic changes consistent with those reported in clinical studies of familial cases of PD. Lastly, a pilot study was conducted to explore the utility of biochemical detection of α- synuclein in nasal secretions, in combination with a smell test, as potential early- biomarkers of PD. The protein, found in great abundance in olfactory regions, was successfully detected at higher levels in nasal secretions compared to salivary samples. The University of Pennsylvania smell identification test (UPSIT) was used to detect olfactory impairment in a cohort of patients and controls, and its applicability within Ireland has been discussed in detail. Collectively, the results presented here highlight the involvement of DOPAL as a contributing cause of Parkinson’s progression and open the possibility of early detection of PD, by monitoring OB pathology using molecular and functional assays. This novel experimental platform shows great promise as an innovative, easy and accessible technology for the development of new restorative and regenerative treatments for PD, raising the enticing possibility of early-stage intervention.2023-11-0