Segmental progression of cardinal motor symptoms in Parkinson's disease: A pilot study suggesting a practical approach to rate disease course in the early stages

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.

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Identification of Blood-based Biomarkers for Early Stage Parkinson’s Disease

10.1101/2020.10.22.20217893 ◽

2020 ◽

Author(s):

Andrew Gao

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Cellular Response ◽

Molecular Mechanisms ◽

Early Stage ◽

Differentially Expressed ◽

Motor Symptoms ◽

Early Stages

AbstractParkinson’s disease (PD) affects millions of people worldwide and causes symptoms such as bradykinesia and disrupted speech. Parkinson’s disease is known to be characterized by the mass death of dopaminergic neurons in the substantia nigra region. In the status quo, PD is often diagnosed at late stages because obvious motor symptoms appear after the disease has progressed far. It is advantageous to diagnose PD before the onset of motor symptoms because treatments are often more effective at early stages. While motor symptoms usually manifest when over 50% of dopaminergic neurons in the substantia nigra are already lost, molecular signatures of PD may be present at early stages in patient blood. This study aimed to analyze several gene expression studies’ data for commonly differentially expressed genes (DEGs) in the blood of early stage PD patients. 147 DEGs were identified in at least two out of three datasets and passed cut-off criteria. A protein interaction network for the DEGs was constructed and various tools were used to identify network characteristics and hub genes. PANTHER analysis revealed that the biological process “cellular response to glucagon stimulus” was overrepresented by almost 21 times among the DEGs and “lymphocyte differentiation” by 5.98 times. Protein catabolic processes and protein kinase functions were also overrepresented. ESR1, CD19, SMAD3, FOS, CXCR5, and PRKACA may be potential biomarkers and warrant further study. Overall, the findings of the present study provide insights on molecular mechanisms of PD and provide greater confidence on which genes are differentially expressed in PD. The results also are additional evidence for the role of the immune system in PD, a topic that is gaining interest in the PD research community.

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