Mitral cells and the glucagon-like peptide 1 receptor: The sweet smell of success?

Abstract

The olfactory bulb (OB) is often affected at very early stages of neurodegenerative disorders, in the so-called “prodromal” phase. In Parkinson's disease (PD), olfactory disturbances appear years before motor symptoms arise. Additionally, pathological alpha-synuclein aggregates are found in olfactory regions before spreading to other areas of the brain. Being positioned at the frontier between the brain and a potentially hostile environment, could explain the particular vulnerability of the OB. Mitral cells (MCs), the principal projecting neurons of the olfactory system, are involved in the pathogenesis and in the prion-like progression of PD. They are affected by Lewy pathology and are thought to contribute to the axonal transport of misfolded alpha-synuclein to other regions of the brain. Here, we first describe the main markers reported to distinguish MCs from other olfactory neurons. We focus on the glucagon-like peptide 1 receptor (GLP-1R), a membrane protein specifically expressed in MCs. After summarizing OB pathology, we explore the idea of targeting specifically MCs with GLP-1 or its analogues. Exenatide has shown great promise as a neuroprotective and neurorestorative agent and has been used in a clinical trial for clinical PD. Since GLP-1R activation has the ability to mitigate many facets of prodromal PD pathology, we postulate that once a robust biomarker is in place that is capable of identifying individuals in the prodromal phase of PD, homing in on GLP-1R could assist in deferring, or eradicating to a significant degree, the clinical manifestation of this debilitating human disorder.