Background
Myotonic dystrophy type 1 (DM1), the most common adult form of muscular dystrophy, impacts muscle function and leads to debilitating complications in multiple organ systems. It significantly affects patients’ quality of life and poses substantial challenges for healthcare providers in managing its multifaceted symptoms. Currently, there is no treatment available to slow the progression of DM1, underscoring the urgent need for reliable biomarkers and the identification of altered signaling pathways for developing targeted therapeutic strategies.
Objective
To identify DM1 biomarkers through a comprehensive proteomic evaluation of cerebrospinal fluid (CSF) from patients.
Methods
Proteomic analyses were conducted on cerebrospinal fluid (CSF) samples from DM1 patients (n=11) and healthy controls (n=5) using Olink monoclonal antibody panels. Lasso regression was employed in a supervised machine-learning analysis to identify proteins that differentiated DM1 and healthy control groups. Enrichment analyses using Reactome and KEGG databases identified specifically altered pathways.
Results
A total of 1072 proteins were quantified, revealing six proteins differentially expressed in DM1 patients and healthy controls: CKAP4, SCARF1, NCAM1, CD59, PTH1R, and CA4. Fifteen proteins that distinguished the DM1 and control groups reflected aspects of neuronal health, inflammation, cognitive impairment, skeletal deformities, neuromuscular junction disruption, and cytoskeletal regulation. Notably, we observed dysregulated pathways including IGF transport, MAPK signaling, Rap1 signaling, and PI3K-Akt signaling, indicating that pathways dysregulated in other neuromuscular disorders also contribute to DM1 pathophysiology.
Conclusions
This study represents the first exploratory CSF proteomic profiling of DM1 using multiple Olink panels, highlighting dysregulated protein pathways that may enhance our understanding of the disease development and inform future therapeutic strategies. For example, the proteomic evidence of altered IGF transport, in addition to the known mis-splicing of the insulin receptor in DM1, suggests that this important pathway, which is known to impact muscle growth, could underlie some aspects of muscle weakness and atrophy in DM1. In addition to clarifying these dysregulated pathways in DM1, proteomic biomarkers can serve as diagnostic indicators, markers of disease activity, and measures of therapeutic response.