Introduction
Parkinson’s disease (PD) is a degenerative disease of the central nervous system that is commonly observed in middle-aged and elderly people and has been proven to be related to the deposition of Lewy bodies. α-Synuclein (α-syn) is the main component of Lewy bodies, and therefore, α-syn is closely related to PD. Recent studies have shown that arylsulfatase A (ARSA) is associated with PD and may participate in the aggregation and transmission of α-syn through its molecular chaperone function [
1]. PD combined with cognitive impairment (PD-CI) is common in the middle and late stages of PD, and 80% of PD patients will eventually develop Parkinson’s disease dementia (PDD) [
2]. Plasma ARSA levels are associated with motor symptoms and decrease with disease progression. PDD seriously affects the life and work of PD patients and increases disability and mortality rates. In addition, plasma ARSA levels are associated with cognitive function [
3]. Some studies [
4,
5] have not identified PD-related ARSA variants in the Chinese Han population through gene-sequencing analysis. At present, research results on the relationship between ARSA levels and PD are not consistent. To date, no clear and effective biological markers of PDD have been identified except that the amyloid β level of PDD patients is lower than that of PD patients with normal cognitive function [
6,
7]. Therefore, this study quantitatively assessed the relationship between plasma ARSA concentrations and cognitive impairment in PD patients and measured the plasma concentrations of α-syn and their correlation with PD nonmotor symptoms.
Discussion
At present, the etiology of PD is still unclear. Mitochondrial dysfunction, oxidative stress, disordered lipid metabolism, lysosomal dysfunction, excessive neuroinflammation, disordered microbiota, and other possible mechanisms may underlie the pathogenesis of PD [
11]. The neuropathological characteristics of PD include the production of α-syn, which aggregates into Lewy bodies and accumulates in nerve cells; these α-syn aggregates are harmful to dopaminergic neurons in the central nervous system and may trigger the formation of toxic α-syn, which is passed from affected cells to neighboring cells, leading to cell death [
12,
13]. In addition, α-syn is degraded via the proteasomal/autophagosomal pathways [
14]. These pathways themselves can impair lysosomal function, and any damage to the clearance pathway may lead to further α-syn transmission [
15], creating a vicious cycle. In addition, lysosomal dysfunction has been shown to lead to intercellular aggregation, diffusion, and transmission of α-syn [
16].
Many recent studies [
17,
18] have revealed a relationship between lysosomal storage disorders and common neurodegenerative diseases, the most common example of which is the relationship between GBA1 mutations and PD. Recessive mutations in the GBA gene, which encodes glucocerebrosidase, a lysosomal hydrolase, are responsible for Gaucher disease, and carriers of heterozygous GBA mutations have a significantly higher incidence of PD than the general population. However, a study [
19] has shown that with or without mutations in the GBA or LRRK2 genes, lower glucocerebrosidase activity can be observed in PD patients than in healthy individuals. It has been speculated that glucocerebrosidase is a protective factor against PD. ARSA is a lysosomal hydrolase that converts thiaminic acid to galactosylceramide. Mutations in the ARSA gene often cause autosomal recessive lysosomal storage disorder. Allochromatic leukodystrophy is an autosomal lysosomal storage disorder [
20]. ARSA has been shown to be a molecular chaperone of α-syn that inhibits α-syn secretion, aggregation, and transmission through its molecular chaperone function [
1].
In this study, we found that there was no correlation between plasma ARSA and α-syn levels in PD patients. The reason may be that the plasma concentrations of ARSA and α-syn were measured in this study, and α-syn is present mainly in the cytoplasm; therefore, the binding of ARSA and α-syn also occurs mainly in the cytoplasm, and the effect may not be apparent in the plasma. ARSA-specific antibodies or normal IgG have been used as a negative control to conduct α-syn immunoprecipitation, and a large amount of ARSA was found in the cytoplasm and vesicles; this result indicated that ARSA can directly bind to α-syn, and most of the intermediate binding occurs in the cytoplasm. ARSA is widely expressed in brain and spinal cord cells, blood lymphocytes, and peripheral tissue cells, and can also be secreted by cells [
21]. Binding and expression in plasma require further investigation [
1]. However, the changes in plasma ARSA levels in PD and PDD patients suggest that ARSA in the plasma is indeed involved in the pathogenesis of PD.
Previous studies [
5] have shown that the L300S heterozygous mutation of the ARSA gene may be a risk factor for PD; however, the N352S variant does not reduce the activity of the ARSA enzyme and acts as a molecular chaperone of α-syn to inhibit the aggregation and diffusion of α-syn, playing a protective role. A large genetic sequencing study [
4] found that ARSA variants showed no association with PD susceptibility or cognitive impairment. In this study, we explored the correlation between plasma ARSA protein levels and PD course and cognitive impairment; this correlation may occur due to possible regulatory effects on ARSA translation, resulting in differences in the protein level. The small sample size in this study may also be the reason for the inconsistency with the above research results.
This study showed that the plasma ARSA levels in PD patients were related to the H-Y stage and that the ARSA concentrations of patients with early PD were higher than those of healthy controls. With the gradual progression of the disease, the ARSA concentrations gradually decreased. It can be speculated that ARSA may be a protective factor against PD and is related to degeneration of the substantia nigra and striatum. ARSA may compensate for the autophagic clearance of α-syn in neurons, which gradually becomes insufficient with the progression of the disease; thus, ARSA levels gradually decrease. In PD, one-third of patients with higher glucosidase levels had a longer course of the disease, which may be described as a milder disease, and the activity of glucosidase may serve as a marker of PD severity [
19]. A study [
3] pointed out that the ARSA levels in the body were related to the course of the disease and that the ARSA levels and duration of the disease showed an inverted U-shaped trend, reaching a peak approximately 2 years after onset, which is consistent with this study. Additionally, research [
5] has identified ARSA genetic variations among the Han population in China and in PD patients, which means that PD patients with ARSA mutations are rarely identified; therefore, more large-scale case–control studies need to be conducted in familial and sporadic PD or other populations to determine whether the ARSA gene is associated with the incidence of PD [
22].
In this study, the plasma ARSA concentrations were lower in the PD-CI group than in the PD-NCI group. In the correlation analysis, the ARSA concentrations were positively correlated with the MMSE scores. Consistent with this study, Lee J.S. et al. [
1] confirmed that plasma ARSA concentrations were lower in PDD patients. Plasma ARSA levels were positively correlated with overall cognitive ability, total MMSE scores, and scores in various cognitive domains. In one study, mice were injected with lentiviral vectors expressing hemagglutinin- or green fluorescent protein-labeled ARSA cDNA, and a significant accumulation of ARSA activity was observed on both sides of the hippocampus, suggesting that ARSA is associated with cognitive function [
23].
When we further investigated the correlations between the ARSA levels and MMSE sub-item scores, ARSA levels were found to be positively correlated with three sub-items: orientation to time and place, divided attention, and delayed recall. Studies have shown that among patients with mild cognitive impairment, cognitive impairment is mainly related to time and spatial orientation, attention and language [
24]. In this study, the delayed recall was impaired in PD patients with low ARSA concentrations, which may have occurred because the sample population in this study included patients with mild cognitive impairment and dementia, and with the increase in the severity of cognitive impairment, the delayed recall was gradually impaired.
In this study, plasma α-syn concentrations were higher in the PD-CI patients than in the PD-NCI patients, and the levels in these patients were higher than those in the HCs, suggesting that higher plasma α-syn concentrations are associated with increasingly poor cognitive abilities. In addition, a recent study showed that a specific genetic haplotype in intron 4 in the SNCA gene was associated with the risk of PDD [
25]. Studies have confirmed that high levels of α-syn in plasma are associated with cognitive impairment in PD patients [
26,
27].
In conclusion, plasma ARSA levels are increased in the early stage of PD and decrease gradually with the progression of the disease. Low plasma concentrations of ARSA and high concentrations of α-syn are associated with cognitive impairment in PD patients, and plasma ARSA levels are negatively correlated with the H-Y stage. Based on this conclusion, ARSA may serve as a biomarker for the early diagnosis of PD and may be involved in the mechanism underlying the cognitive impairment of PD patients.
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