Pathogenetic Involvement of Autophagy and Mitophagy in Primary Progressive Multiple Sclerosis

Abstract

Primary progressive multiple sclerosis (PPMS) affects a subset of MS patients and is characterised by continuous progression from the onset. The molecular mechanisms underlying PPMS are poorly understood, and therapeutic options are limited, with no specific markers for early detection and monitoring. This study investigated the roles of autophagy and mitophagy in PPMS. We found that autophagy markers (ATG5 and ATG7) and mitophagy markers (Parkin and Optineurin) were significantly reduced in the serum of PPMS patients compared to control and relapsing-remitting MS (RRMS) individuals. This reduction was associated with an increase in markers indicative of neurodegeneration and mitochondrial dysfunction. Additionally, a positive correlation between autophagy and mitophagy proteins in the PPMS group suggests that these mechanisms are reciprocally associated and modulated in PPMS. Our investigation reveals that autophagy and mitophagy are actively involved in PPMS and exhibit distinct patterns across MS subtypes. Measurements of circulating components related to autophagy and mitophagy could serve as potential biomarkers for early PPMS detection.

Keywords: ATG5; ATG7; GFAP; Optineurin; Parkin; biomarker; lactate; serum.

FIGURE 1

(A–D) Levels of ATG5 (A), ATG7 (B), Parkin (C) and OPTN (D) in the sera of patients with primary progressive multiple sclerosis (PPMS), relapsing remitting multiple sclerosis (RRMS) and healthy individuals (CTRL). The boxes represent the interquartile range (25th–75th percentile). The line within the box denotes the median. The vertical lines extending from the boxes indicate the range of values. (E–H) Spearman's rank correlation analysis between the levels of autophagy markers ATG5 and ATG7 and the mitophagy markers OPTN and Parkin in MS patients affected by PPMS.