α-Synuclein Pathology and Reduced Neurogenesis in the Olfactory System Affect Olfaction in a Mouse Model of Parkinson's Disease

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 STATEMENTOlfactory 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.

Amelioration of olfactory dysfunction in a mouse model of Parkinson’s disease via enhancing GABAergic signaling

“…Firstly, the regeneration of interneurons in the OB occurs over a lifetime, and migrating neuroblasts from the SVZ differentiate into mature interneurons in the OB [ 22 , 40 ]. We observed fewer adult-born neurons in the OB, supported by the similar pathologic changes in A30P-transgene and MPTP inducible mice [ 20 , 41 , 42 ]. However, the impaired adult neurogenesis is insufficient to affect the total number of multiple interneurons at the testing time.…”

“…Additionally, we further determined that the weakness of inward GABAergic inhibition was at least partly responsible for the hyperactivity of M/Ts. Consistent with this, it is known that the GCL and internal plexiform layer (IPL) in OB mainly contain diverse interneurons, and α-synuclein is expressed predominantly in neuronal fibers of the GCL and IPL of the OB at the early stage of PD [ 20 , 34 , 35 ]. These researches imply that, the GABAergic dysfunction in OB is strongly related to α-synuclein pathology and might be the direct factor of olfactory impairments at the early stage of PD.…”

“…Based on the dual-hit hypothesis of PD, α-synuclein is triggered in the OB and subsequently spreads to other areas [ 10 ]. Recent evidence has demonstrated that OB is susceptible to α-synuclein and that α-synuclein aggregates restricted to the OB can induce olfactory impairment, strongly suggesting that α-synuclein in the OB is closely correlated with olfactory dysfunction [ 16 , 20 ]. Therefore, we further investigated the spatial distribution characteristics of α-synuclein in the OB by immunostaining in SNCA-A53T and WT mice.…”

“…Olfactory dysfunction is a cardinal prodromal symptom of various neurodegenerative disorders, including PD, and the olfactory pathway is especially vulnerable to α-synuclein pathology [ 4 , 20 ]. However, the precise synaptic mechanisms underlying neural microcircuit disharmony in the primary olfactory pathway at the early stage of PD remain incompletely understood.…”

“…In particular, α-synuclein BAC transgenic mice, a model of prodromal PD, could exhibit hyposmia with native α-synuclein expression patterns in OB [ 24 ]. Similarly, transgenic mice overexpressing α-synuclein with A53T or A30P mutants displayed olfactory dysfunction and α-synuclein pathology in OB before the onset of motor symptoms [ 11 , 20 ]. In PD patients, α-synuclein was found throughout the OB [ 25 – 27 ].…”