Different reactive profiles of calmodulin in the CSF samples of Chinese patients of four types of genetic prion diseases

Xiao-Xi Jia; Chao Hu; Cao Chen; Li-Ping Gao; Dong-Lin Liang; Wei Zhou; Run-Dong Cao; Kang Xiao; Qi Shi; Xiao-Ping Dong

doi:10.3389/fnmol.2024.1341886

Different reactive profiles of calmodulin in the CSF samples of Chinese patients of four types of genetic prion diseases

Front Mol Neurosci. 2024 Feb 8:17:1341886. doi: 10.3389/fnmol.2024.1341886. eCollection 2024.

Authors

Xiao-Xi Jia^#¹, Chao Hu^#^{1

2}, Cao Chen^#^{1

3}, Li-Ping Gao¹, Dong-Lin Liang¹, Wei Zhou¹, Run-Dong Cao¹, Kang Xiao¹, Qi Shi^{1

4}, Xiao-Ping Dong^{1

3

4

5}

Affiliations

¹ National Key-Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
² Xuanwu Hospital Capital Medical University, Beijing, China.
³ Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
⁴ China Academy of Chinese Medical Sciences, Beijing, China.
⁵ Shanghai Institute of Infectious Disease and Biosafety, Shanghai, China.

^# Contributed equally.

Abstract

Background and purpose: Calmodulin (CaM) levels exhibit significant elevation in the brain tissue of rodent and cell line models infected with prion, as well as in the cerebrospinal fluid (CSF) samples from patients diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD). However, the status of CSF CaM in patients with genetic prion diseases (gPrDs) remains unclear. This study aims to assess the characteristics of CSF CaM in Chinese patients presenting four subtypes of gPrDs.

Methods: A total of 103 CSF samples from patients diagnosed with T188K-gCJD, E200K-gCJD, D178N-FFI, P102L-GSS were included in this study, along with 40 CSF samples from patients with non-prion diseases (non-PrDs). The presence of CSF CaM and 14-3-3 proteins was assessed using Western blots analysis, while levels of CSF 14-3-3 and total tau were measured using enzyme-linked immunosorbent assays (ELISAs). Statistical methods including multivariate logistic regression were employed to evaluate the association between CSF CaM positivity and relevant clinical, laboratory, and genetic factors.

Results: The positive rates of CSF CaM were significantly higher in cases of T188K-gCJD (77.1%), E200K-gCJD (86.0%), and P102-GSS (90.9%) compared to non-PrD cases (22.5%). In contrast, CSF CaM positivity was slightly elevated in D178N-FFI (34.3%). CSF CaM positivity was remarkably high in patients who tested positive for CSF 14-3-3 by Western blot and exhibited high levels of total tau (≥1400 pg/ml) as measures by ELISA. Multivariate logistic regression analysis confirmed a significant association between CSF CaM positivity and specific mutations in PRNP, as well as with CSF 14-3-3 positivity. Furthermore, the diagnostic performance of CaM surpassed that of 14-3-3 and tau when analyzing CSF samples from T188K-gCJD and E200K-gCJD patients.

Conclusion: Western blot analysis reveals significant variations in the positivity of CSF CaM among the four genotypes of gPrD cases, demonstrating a positive correlation with 14-3-3 positivity and elevated tau levels in CSF.

Keywords: 14-3-3; calmodulin; cerebrospinal fluid; genetic prion diseases; tau.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by SKLID Development Grants (2021SKLID504, 2019SKLID401, 2019SKLID603, and 2021SKLID503) from the State Key Laboratory for Infectious Disease Prevention and Control, China CDC.