Abstract
Background: Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is the most common type of autosomal dominant ataxia. Like other neurodegenerative diseases, is characterized by the dysfunction of the protein quality control (PQC) system. The carboxyl terminus of the Hsp70-interacting protein (CHIP), an important component of PQC, participates in the clearance of misfolded proteins to maintain cellular homeostasis. While no cure for SCA3 exists, the disease progresses slowly. Thus, the identification of biomarkers that indicate the severity and prognosis of this disease would be valuable.Methods: In this exploratory case-control study, we quantitatively evaluated the concentrations of CHIP in the sera of 80 patients with SCA3 and 80 age and sex-matched controls, using the enzyme-linked immunosorbent assay (ELISA). CHIP levels in the cerebrospinal fluid (CSF) donated by six patients and six healthy volunteers, who were matched for sex and age were also measured. All the baseline data were collected, and the patients underwent clinical evaluation. The correlations between CHIP levels and several clinical measurements were analyzed.Results: The serum CHIP level in the SCA3 group was (80.93 ± 28.68) ng/mL, which was significantly higher than those in the control group [(40.37 ± 18.55) ng/mL]. Similar results were observed for the CSF [(164.59 ± 42.99) ng/mL and (37.47 ± 7.85) ng/mL, respectively]. CSF CHIP levels were significantly higher than the serum CHIP levels in the SCA3 group but not in the control group. The Dunn-Bonferroni post-hoc for Kruskal-Wallis test revealed no significant difference between the serum and CSF of the patients and the control group. Multivariate linear regression showed that serum CHIP levels correlated positively with disease severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Moreover, we found that serum CHIP levels were moderately correlated with age in healthy controls.Conclusion: The present study determined that CHIP levels increased significantly in the serum and CSF of patients with SCA3 and that serum CHIP levels were corelated with disease severity. Thus, CHIP is a promising biomarker for SCA3.
Highlights
Spinocerebellar ataxia type 3 (SCA3), named MachadoJoseph disease (MJD), is considered to be the most common form of autosomal dominant ataxia [1]
The clinical and molecular data of SCA3 patients and controls were presented as mean ± standard deviation (SD) (Table 1)
In the stepwise multivariate linear regression, the SARA and International Cooperative Ataxia Rating Scale (ICARS) scores showed separate correlations in the regression models (SARA: standardized β-coefficient = 0.500, p = 0.034; ICARS: standardized βcoefficient = 0.561, p = 0.015), while age, Age at onset (AAO), Disease duration (DD), CAG repeats numbers were withdrawn from the model
Summary
Spinocerebellar ataxia type 3 (SCA3), named MachadoJoseph disease (MJD), is considered to be the most common form of autosomal dominant ataxia [1]. The disease is caused by an expansion of the CAG trinucleotide beyond 52 repeats in the ATXN3 gene [2]. Monitoring the progress of the disease is important. Biomarkers have important clinical applications in diagnosing and monitoring the disease, as well as evaluating the efficacy of treatments [5]. The identification of biomarkers for SCA3 is essential. Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is the most common type of autosomal dominant ataxia. While no cure for SCA3 exists, the disease progresses slowly. The identification of biomarkers that indicate the severity and prognosis of this disease would be valuable
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