Study Uncovers Biological Mechanism Behind Loss of Smell in Parkinson’s Patients

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"About 75-90 percent of Parkinson’s patients report diminishing sense of smell, even prior to the onset of motor symptoms, and is now recognized a non-motor symptom of Parkinson’s disease.

Researchers ... determined the biological mechanisms behind this olfactory impairment by using an alpha-synuclein A30P mouse model used to mimic symptoms of Parkinson’s in mice.

Using buried food tests, the researchers found that the mice with later stage symptoms of Parkinson’s disease exhibited olfactory impairment. They found that those mice with olfactory deficits exhibited severe pathology in projection neurons of the olfactory pathway. They also found these mice showed reduced neurogenesis in the olfactory bulb. In contrast, studies have shown that healthy aging brains continue to form new neurons in the olfactory bulb throughout life. ..."

From the abstract:

"Parkinson's disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathologic changes in the olfactory pathway of transgenic (Tg) mice of both sexes expressing the human A30P mutant α-synuclein (α-syn; α-syn-Tg mice) at 6–7 and 12–14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons (PNs) of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at six to seven months and OB periglomerular cells at 12–14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endocytic and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12–14 months. Our data suggest that
(1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD;
(2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology;
(3) α-syn pathology is restricted to projection neurons in the olfactory pathway;
(4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and
(5) synaptic endocytosis and exocytosis defects in the OB may further explain olfactory deficits.

SIGNIFICANCE STATEMENT Olfactory dysfunction is a characteristic symptom of Parkinson's disease (PD). Using the human A30P mutant α-synuclein (α-syn)-expressing mouse model, we demonstrated the appearance of olfactory deficits at late stages of the disease, which was accompanied by the accumulation of α-syn pathology in projection neurons (PNs) of the olfactory system. This dysfunction included a reduction in olfactory bulb (OB) neurogenesis as well as changes in synaptic vesicular transport affecting synaptic function, both of which are likely contributing to olfactory behavioral deficits."

Study Uncovers Biological Mechanism Behind Loss of Smell in Parkinson’s Patients < Neurosurgery

α-Synuclein Pathology and Reduced Neurogenesis in the Olfactory System Affect Olfaction in a Mouse Model of Parkinson's Disease (no public access)