Abstract
Parkinson’s disease (PD) is a prevalent motor disease caused by the accumulation of mutated α-synuclein (α-Syn); however, its early stages are also characterized by non-motor symptoms, such as olfactory loss, cognitive decline, depression, and anxiety. The therapeutic effects of environmental enrichment (EE) on motor recovery have been reported, but its effects on non-motor symptoms remain unclear. Herein, we reveal the beneficial effects of EE on PD-related non-motor symptoms and changes in synaptic plasticity in the nucleus accumbens. To investigate its therapeutic effects in the early phase of PD, we randomly assigned eight-month-old mice overexpressing human A53T (hA53T) α-Syn to either the EE or standard condition groups for two months. Next, we performed behavioral tests and biochemical and histological analyses at 10 months of age. EE significantly alleviated locomotor hyperactivity and anxiety during the early stages of PD. It normalized the levels of tyrosine hydroxylase, phosphorylated and oligomeric α-Syn, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex-forming proteins, including synaptosomal-associated protein, 25 kDa, syntaxin1, and vesicle-associated membrane protein 2 (VAMP2). Moreover, the interactions between VAMP2 and pSer129 α-Syn were markedly reduced following EE. The restoration of synaptic vesicle transportation status may underlie the neuroprotective effects of EE in hA53T α-Syn mice.
Highlights
Alpha-synuclein (α-Syn) is the main constituent of the neuropathological lesions found in patients with Parkinson’s disease (PD), Lewy body dementia, multiple system atrophy, and other disorders collectively known as α-synucleinopathies [1,2,3]
Motor function tests were performed to determine whether motor symptoms appeared in human A53T (hA53T) α-Syn mice at 10 months of age
There were no significant differences in the grip strength and hanging wire tests between the PD-standard cages (SC) and PD-EE groups, whereas there were significant differences in those between the WT-SC and WT-EE groups
Summary
Alpha-synuclein (α-Syn) is the main constituent of the neuropathological lesions found in patients with Parkinson’s disease (PD), Lewy body dementia, multiple system atrophy, and other disorders collectively known as α-synucleinopathies [1,2,3]. Alphasynuclein (α-Syn) is a protein that is widely distributed in the presynaptic nerve terminal, and its role has not yet been fully elucidated. The number of presynaptic vesicles decreases when α-Syn levels decrease in primary hippocampal neurons [4]. Aggregated α-Syn acts as a negative regulator of neurotransmitter release in mice expressing mutant human α-Syn [5,6]. Normal levels of α-Syn assist with vesicle trafficking, α-Syn overexpression interferes with vesicle trafficking [7] and neurotransmitter release by inhibiting the recycling of synaptic vesicle proteins [8,9]. Α-Syn directly binds to synaptobrevin-2, vesicle-associated membrane protein 2 (VAMP2) [10], and acidic lipidcontaining membranes [11] Normal levels of α-Syn assist with vesicle trafficking, α-Syn overexpression interferes with vesicle trafficking [7] and neurotransmitter release by inhibiting the recycling of synaptic vesicle proteins [8,9]. α-Syn directly binds to synaptobrevin-2, vesicle-associated membrane protein 2 (VAMP2) [10], and acidic lipidcontaining membranes [11]
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