The Olfactory Trail of Neurodegenerative Diseases

Abstract

Alterations in olfactory functions are proposed as possible early biomarkers of neurodegenerative diseases. Parkinson's and Alzheimer's diseases manifest olfactory dysfunction as a symptom, which is worth mentioning. The alterations do not occur in all patients, but they can serve to rule out neurodegenerative pathologies that are not associated with small deficits. Several prevalent neurodegenerative conditions, including impaired smell, arise in the early stages of Parkinson's and Alzheimer's diseases, presenting an attractive prospect as a snitch for early diagnosis. This review covers the current knowledge on the link between olfactory deficits and Parkinson's and Alzheimer's diseases. The review also covers the emergence of olfactory receptors as actors in the pathophysiology of these diseases. Olfactory receptors are not exclusively expressed in olfactory sensory neurons. Olfactory receptors are widespread in the human body; they are expressed, among others, in the testicles, lungs, intestines, kidneys, skin, heart, and blood cells. Although information on these ectopically expressed olfactory receptors is limited, they appear to be involved in cell recognition, migration, proliferation, wound healing, apoptosis, and exocytosis. Regarding expression in non-chemosensory regions of the central nervous system (CNS), future research should address the role, in both the glia and neurons, of olfactory receptors. Here, we review the limited but relevant information on the altered expression of olfactory receptor genes in Parkinson's and Alzheimer's diseases. By unraveling how olfactory receptor activation is involved in neurodegeneration and identifying links between olfactory structures and neuronal death, valuable information could be gained for early diagnosis and intervention strategies in neurodegenerative diseases.

Keywords: Alzheimer’s disease; Parkinson’s disease; ectopic expression; microglia; neurons; olfactory receptors.

Figure 1

Schematic representation of the olfactory system. Odorants arrive at the nasal mucosa (1), and progress towards the olfactory receptors in the cilium (2). Neurons containing olfactory receptors transmit the information from the cilium to the olfactory bulb via the glomeruli (3). The olfactory bulb receives and decodes the information. The processed data are then directly dispatched to the limbic system (involving the amygdala and hippocampus) and the neocortex for further information processing. Olfactory receptor-related alterations reported for the main neurodegenerative diseases are as summarized (right).

Figure 2

Schematic representation of a G protein-coupled receptor. Panel (A), diagram showing the seven transmembrane (TM) α-helices, α helix 8 (H8), N-terminal (N-t) extracellular-facing domain and C-terminal (C-t) cytoplasmic-facing domain. G protein-coupled receptors are associated with heterotrimeric G protein (with α, ß and γ subunits). Panel (B), two-dimensional representation of a G protein-coupled receptor; the seven TM α-helices are connected by intracellular (ICL1–ICL3) and extracellular (ECL1–ECL3) loops. Panel (C), three-dimensional structure of a receptor coupled with a G protein with α (fuchsia), ß (blue) and γ (green) subunits (from PDB Protein Database, structure identification number: 6D9H).

Figure 3

Sequence comparison of some olfactory receptors and the adenosine A₃ receptor, which is a class A G protein-coupled receptor expressed in virtually all organs and tissues. Sequences of the olfactory receptors mentioned in this review are aligned with that of the human adenosine A₃ receptor. Notice the presence of seven transmembrane α-helices in all cases (TM1 to TM7; underlined in red) and the highly conserved residues; conserved cysteines are in yellow and other conserved residues are in blue (some substitutions can be found for some of the olfactory receptors in these highly conserved positions).