Noncanonical Roles of hα-syn (A53T) in the Pathogenesis of Parkinson’s Disease: Synaptic Pathology and Neuronal Aging

Abstract

The motor and nonmotor symptoms of PD involve several brain regions. However, whether α-syn pathology originating from the SNc can directly lead to the pathological changes in distant cerebral regions and induce PD-related symptoms remains unclear. Here, AAV9-synapsin-mCherry-human SNCA (A53T) was injected into the unilateral SNc of mice. Motor function and olfactory sensitivity were evaluated. Our results showed that AAV9-synapsin-mCherry-human SNCA was continuously expressed in SNc. The animals showed mild motor and olfactory dysfunction at 7 months after viral injection. The pathology in SNc was characterized by the loss of dopaminergic neurons accompanied by ER stress. In the striatum, hα-syn expression was high, CaMKβ-2 and NR2B expression decreased, and active synapses reduced. In the olfactory bulb, hα-syn expression was high, and aging cells in the mitral layer increased. The results suggested that hα-syn was transported in the striatum and OB along the nerve fibers that originated from the SNc and induced pathological changes in the distant cerebral regions, which contributed to the motor and nonmotor symptoms of PD.

α-Synuclein aggregation in the olfactory bulb induces olfactory deficits by perturbing granule cells and granular–mitral synaptic transmission

“…It has been reported that α-synuclein accumulation reduces GABAergic inhibitory transmission in a model of multiple system atrophy 41 . Consistent with our findings, a recent study found that α-synuclein aggregation induced a reduction in presynaptic membrane area 5 , likely due to binding of α-synuclein aggregates with microtubule beta-III to form an insoluble complex. This complex may also regulate release of synaptic vesicles in GABAergic interneurons 41 .…”

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

“…Typically, changes in the amplitude of mini postsynaptic currents represent alterations in postsynaptic effects, whereas frequency changes are largely due to the release of presynaptic neurotransmitters. It has been reported that α-synuclein deposits can induce structural and functional damage in the presynaptic area [ 36 – 39 ]. We thus assessed the factors influencing presynaptic effects, including the overall interneurons and the complex synaptic proteins.…”

Synthesis and Characterization of Click Chemical Probes for Single-Cell Resolution Detection of Epichaperomes in Neurodegenerative Disorders

“…The accumulation of aggregated and insoluble S129 phosphorylated α-synuclein in these mice follows a similar accumulation as that observed in humans with synucleinopathy. Reactive gliosis and mitochondrial alterations are also evident in various brain regions, along with synaptic dysfunction in the hippocampus, which may contribute to cognitive deficits [ 39 , 40 ]. These mice were bred on a C57BL/C3H background to produce transgenic homozygous and wildtype littermates.…”