Proteomic studies in the discovery of cerebrospinal fluid biomarkers for amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative motor neuron disease, which usually leads to death within a few years. The diagnosis is mainly based on clinical symptoms and there is a need for ALS-specific biomarkers to make an early and precise diagnosis, for development of disease-modifying drugs and to gain new insights into pathophysiology. Areas covered: In the present review, we summarize studies using mass spectrometric (MS) approaches to identify protein alterations in the cerebrospinal fluid (CSF) of ALS patients. In total, we identified 11 studies fulfilling our criteria by searching in the PubMed database using the keywords 'ALS' and 'CSF' combined with 'proteome', 'proteomic', 'mass spectrometry' or 'protein biomarker'. Ten proteins were differently regulated in ALS CSF compared to controls in at least 2 studies. We will discuss the relevance of the identified proteins regarding the frequency of identification, extent of alteration and brain-specificity. Expert commentary: Most of the identified CSF biomarker candidates are irreproducible or mainly blood-derived. We assign the missing success of CSF proteomic studies in biomarker discovery to a lack of sensitivity, unsuitable normalization, low quality assurance and variations originating from sample preparation. These issues must be improved in future proteomic studies in CSF.

Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation

“…Proteomics analysis of FTD and ALS has been conducted primarily in CSF with limited reproducibility across studies 16,[28][29][30][31] . To date, no studies have been reported for FTD using serum or plasma.…”

Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies

“…A growing body of literature, including various proteomic studies, has helped to demonstrate that CSF composition in ALS may be abnormal ( Barschke et al , 2017 ; Blasco et al , 2017 ; Hayashi et al , 2019 ). This includes findings of raised TDP-43 and neurofilament levels, as well as an altered inflammatory profile ( Majumder et al , 2018 ; Schreiber et al , 2018 ; Gille et al , 2019 ).…”

Simultaneous Improvement in the Precision, Accuracy, and Robustness of Label-free Proteome Quantification by Optimizing Data Manipulation Chains*

“…On one hand, a variety of powerful quantification tools integrating novel align-ment and feature generation methods have been constructed to maximally fill in missing blanks and elevate the reproducibility of LFQ (17)(18)(19). On the other hand, many computational algorithms have been proposed to minimize the instrumental and experimental fluctuations (5), enhance the stability of the identified candidate markers (20), and reduce the extremely large dynamic range of the protein abundance (21). Specifically, Ն18 quantification software tools and Ն3 transformation, Ն18 pretreatment, and Ն7 missing-value imputation methods have been proposed and sequentially integrated into the quantification workflow to overcome the above challenges to the extent possible (supplemental Table S1).…”