Altered regulation of serum lysosomal acid hydrolase activities in Parkinson's disease: A potential peripheral biomarker?

Niimi, Yoshiki; Ito, Shinji; Mizutani, Yasuaki; Murate, Kenichiro; Shima, Sayuri; Ueda, Akihiro; Satake, Wataru; Toda, Tatsushi; Mutoh, Tatsuro

doi:10.1016/j.parkreldis.2018.10.032

Cited by 18 publications

(21 citation statements)

References 29 publications

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“…Several studies have shown a heterogeneous level of lysosomal enzyme activities in fluid biomarker or brain tissue in patients with PD. Glucocerebrosidase activity is consistently lower in the blood 13 , CSF 7 , or brain tissue 14 in patients with PD than in normal controls, whereas the activities of serum and CSF β-galactosidase or CSF β-hexosaminidase are increased 8,9,15 . Considering that varying levels of lysosomal enzyme activity were found in patients with PD with a wide range of disease duration, dynamic change in the activity of each lysosomal enzyme as PD progresses must be investigated.…”

Section: Discussionmentioning

confidence: 89%

“…Considering that many genes known as risk factors for PD are relevant for intracellular transport pathway to lysosomes or lysosomal function 6 , defects in this system and consequent accumulation of aggregated protein play a primary role in the pathogenesis of PD. Accordingly, studies have identified the fluid biomarker of lysosomal enzymes to measure the central pathological process in PD [7][8][9] . In particular, patients with PD have reduced level of glucocerebrosidase in the blood and cerebrospinal fluid (CSF), which provides a value in diagnosing PD 7,10 .…”

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confidence: 99%

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Changes in plasma arylsulfatase A level as a compensatory biomarker of early Parkinson’s disease

Yoo

Lee

Chung

et al. 2020

Sci Rep

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Lysosomal dysfunction has been associated with Parkinson’s disease (PD). However, the activity of lysosomal enzymes is heterogeneously observed in PD. We investigated whether arylsulfatase A (ARSA) level can be used as a fluid biomarker of PD and can reflect disease progression. Plasma ARSA level was measured in 55 patients with early and drug-naïve PD, 13 patients with late PD, and 14 healthy controls. We compared the plasma ARSA level among the groups and assessed its correlation to clinical parameters and striatal dopamine transporter (DAT) activity. Plasma ARSA level was not correlated with age. The early PD group had higher plasma ARSA level than the control and late PD groups. In a generalized additive model including all patients with PD, the plasma ARSA level showed an inverted U-shape according to disease duration, peaking at 2.19 years. In patients with early PD, plasma ARSA level was positively correlated to parkinsonian motor score and negatively to striatal DAT activity. In summary, plasma ARSA level was elevated in early stage of PD, and elevated plasma ARSA level was correlated to the clinical and imaging markers of nigrostriatal degeneration. These results suggest that ARSA level is a potential biomarker of compensation in early PD.

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

Changes in plasma arylsulfatase A level as a compensatory biomarker of early Parkinson’s disease

Yoo

Lee

Chung

et al. 2020

Sci Rep

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“…Both α-gal protein levels and enzymatic activity were found to be decreased in leukocytes from iPD patients compared to healthy controls [43,85] . At the same time, the enzymatic activity of α-gal in dried blood spots was found to be either reduced [86] or not different [71,87] in iPD patients, and decreased in GBA mutation carriers [71] . In the same vein with GCase, increased activity was found in LRRK2 mutation carriers [86] , suggesting the possibility that in these cases there is a general compensatory upregulation of lysosomal activity.…”

Section: Other Lysosomal Componentsmentioning

confidence: 85%

“…As with α-gal, the results of its enzymatic activity levels in iPD patients are mixed. There are reports of an increase in serum [87] and CSF [69] , and of no difference again in serum [66] and CSF [66,67] . When compared with α-gal activity, β-gal activity was found to be elevated in serum samples from iPD patients [87] .…”

Section: Other Lysosomal Componentsmentioning

confidence: 97%

Autophagy-lysosome pathway as a source of candidate biomarkers for Parkinson’s disease

Papagiannakis¹,

Stefanis²

2020

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1% of the worldwide population. Diagnosis of PD relies on clinical history and physical examination, but misdiagnosis is common in early stages. Despite considerable progress in understanding PD pathophysiology, including genetic and biochemical causes, diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease-modifying treatments. Increasing evidence suggests that autophagic dysregulation causes the accumulation of abnormal proteins, such as aberrant α-synuclein, a protein critical to PD pathogenesis. Mutations in the GBA gene are a major PD risk factor and β-glucocerebrosidase (GCase) is also emerging as an important molecule in PD pathogenesis. Consequently, proteins involved in the autophagy-lysosome pathway and GCase protein levels and activity are prime targets for the research and development of new PD biomarkers. The studies so far in PD biological material have yielded some consistent results, particularly regarding the levels of Hsc70, a component of the chaperonemediated autophagy pathway, and the enzymatic activity of GCase in GBA mutation carriers. In the future, larger longitudinal studies, corroborating previous research on possible biomarker candidates, as well as extending the search for possible candidates for other lysosomal components, may yield more definitive results.

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“…Reduced GBA activity has been detected in the cerebrospinal fluid of PD patients in comparison to controls [ 43 ] and in the blood of PD patients with and without GBA1 mutations [ 44 ]. The activity of β-galactosidase and β-hexosaminidase, two other lysosomal enzymes, has been detected elevated in the CSF or blood of PD patients [ 43 , 45 , 46 ]. Therefore, it has been hypothesized that other lysosomal enzymes may be differentially expressed or display altered activity in PD patients in comparison to controls, independently of the presence of ARSA gene mutations.…”

Section: Clinical Evidence On the Emerging Role Of Asa In Pdmentioning

confidence: 99%

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

et al. 2020

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Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is a clinically heterogeneous disorder, with obscure etiology and no disease-modifying therapy to date. Currently, there is no available biomarker for PD endophenotypes or disease progression. Accumulating evidence suggests that mutations in genes related to lysosomal function or lysosomal storage disorders may affect the risk of PD development, such as GBA1 gene mutations. In this context, recent studies have revealed the emerging role of arylsulfatase A (ASA), a lysosomal hydrolase encoded by the ARSA gene causing metachromatic leukodystrophy (MLD) in PD pathogenesis. In particular, altered ASA levels have been detected during disease progression, and reduced enzymatic activity of ASA has been associated with an atypical PD clinical phenotype, including early cognitive impairment and essential-like tremor. Clinical evidence further reveals that specific ARSA gene variants may act as genetic modifiers in PD. Recent in vitro and in vivo studies indicate that ASA may function as a molecular chaperone interacting with α-synuclein (SNCA) in the cytoplasm, preventing its aggregation, secretion and cell-to-cell propagation. In this review, we summarize the results of recent preclinical and clinical studies on the role of ASA in PD, aiming to shed more light on the potential implication of ASA in PD pathogenesis and highlight its biomarker potential.

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Altered regulation of serum lysosomal acid hydrolase activities in Parkinson's disease: A potential peripheral biomarker?

Cited by 18 publications

References 29 publications

Changes in plasma arylsulfatase A level as a compensatory biomarker of early Parkinson’s disease

Changes in plasma arylsulfatase A level as a compensatory biomarker of early Parkinson’s disease

Autophagy-lysosome pathway as a source of candidate biomarkers for Parkinson’s disease

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

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