Arylsulfatase A (ASA) in Parkinson’s Disease: From Pathogenesis to Biomarker Potential

Angelopoulou, Efthalia; Paudel, Yam Nath; Clara, Villa; Piperi, Christina

doi:10.3390/brainsci10100713

Cited by 12 publications

(7 citation statements)

References 75 publications

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“…53 Among the CSF proteins differentially expressed between LRRK2+ patients and unaffected LRRK2+ controls, several stood out for their relevance in Parkinson's disease: ARSA, SMPD1, CTSB and TENM4.ARSA is a lysosomal chaperone that prevents alpha-synuclein aggregation, secretion and cell-to-cell propagation. 54 We found ARSA elevated in LRRK2+ patients, which could be interpreted as a protection mechanism to prevent the formation of alpha-synuclein aggregates. CTSB (causal protein, see causal analysis) and SMPD1 play important roles in Parkinson's disease autophagy and lysosomal degradation processes.…”

Section: Genetic Patientsmentioning

confidence: 59%

Parkinson’s disease causality and heterogeneity: a proteogenomic view

Messa

Kaiser

Zhang

et al. 2022

Preprint

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The pathogenesis and clinical heterogeneity of Parkinson’s disease have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of CSF has opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in Parkinson’s disease (1103 patients, 4135 proteins). Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest Parkinson’s disease genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB was previously reported to be upregulated in the substantia nigra of Parkinson’s disease patients. We also compared the CSF proteomes of patients and controls. The Parkinson’s disease cohort comprised not only LRRK2+ and GBA+ mutation carriers but also idiopathic patients. Proteome differences between GBA+ patients and unaffected GBA+ controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. The proteins discriminating LRRK2+ patients from unaffected LRRK2+ controls, revealed dysregulated lysosomal degradation, as well as altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction / oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on the use of previously reported protein-based risk scores. In summary, we: i) identified causal proteins for Parkinson’s disease, ii) assessed CSF proteome differences in Parkinson’s disease patients of genetic and idiopathic etiology, and. iii) stratified idiopathic patients into robust clinically relevant subtypes. Our findings not only contribute to the identification of new therapeutic targets but also to shaping personalized medicine in CNS neurodegeneration.

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Section: Genetic Patientsmentioning

confidence: 59%

Parkinson’s disease causality and heterogeneity: a proteogenomic view

Messa

Kaiser

Zhang

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Among the CSF proteins differentially expressed between LRRK2 + patients and unaffected LRRK2 + controls, several stood out for their relevance in PD: ARSA, SMPD1, CTSB and TENM4. ARSA (causal protein, see causal analysis) is a lysosomal chaperone that prevents alpha-synuclein aggregation, secretion and cell-to-cell propagation 46 . We found ARSA elevated in LRRK2 + patients, which could be interpreted as a protection mechanism to prevent the formation of alpha-synuclein aggregates.…”

Section: Discussionmentioning

confidence: 99%

A proteogenomic view of Parkinson’s disease causality and heterogeneity

Kaiser

Zhang²,

Mollenhauer

et al. 2023

npj Parkinsons Dis.

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The pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into “endotypes”. The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Plasma arylsulfatase A levels are associated with cognitive function in Parkinson’s disease

Shi

et al. 2022

Neurol Sci

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Background Arylsulfatase A (ARSA), a lysosomal enzyme, has been shown to inhibit the aggregation and propagation of α-synuclein (α-syn) through its molecular chaperone function. The relationship between ARSA levels and Parkinson’s disease (PD) in the Chinese Han population remains controversial, and few quantitative research studies have investigated the relationship between plasma ARSA levels and PD. Objectives The purpose of this study was to investigate the relationships between ARSA levels and cognitive function in PD patients and to evaluate the association of ARSA and α-syn levels with nonmotor symptoms. Methods Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma ARSA and α-syn levels in 50 healthy controls, 120 PD patients (61 PD patients with no cognitive impairment (PD-NCI) and 59 PD patients with cognitive impairment (PD-CI)). Motor symptoms and nonmotor symptoms (cognitive function, Unified Parkinson’s Disease Rating Scale (UPDRS) score, depression, anxiety, constipation, olfactory dysfunction, sleep disruption, and other symptoms) were assessed with the relevant scales. The Kruskal–Wallis H test was used for comparison between groups, and Pearson/Spearman analysis was used for correlation analysis. Results The plasma ARSA concentrations were lower in the PD-CI group than in the PD-NCI group. The plasma α-syn levels in the PD-CI group were higher than those in the healthy control group, and the plasma ARSA levels were correlated with the Mini-Mental State Examination (MMSE scores) and Hoehn and Yahr (H-Y) stage. Conclusion We used a quantitative assessment method to show that low plasma ARSA levels and high α-syn levels are related to cognitive impairment in PD patients. Plasma ARSA levels gradually decrease with PD progression.

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Arylsulfatase A (ASA) in Parkinson’s Disease: From Pathogenesis to Biomarker Potential

Cited by 12 publications

References 75 publications

Parkinson’s disease causality and heterogeneity: a proteogenomic view

Parkinson’s disease causality and heterogeneity: a proteogenomic view

A proteogenomic view of Parkinson’s disease causality and heterogeneity

Plasma arylsulfatase A levels are associated with cognitive function in Parkinson’s disease

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