α-Synuclein Promotes the Expression and Release of Neurofilament Light Chain from Oligodendrocytes in a Murine Model: Implication for Multiple System Atrophy?

OBJECTIVE

The understanding of neurofilament light chain (NfL) presence and release in oligodendrocytes is limited. This study aims to determine the NfL expression in oligodendrocytes, investigate whether excess ɑ-synuclein (α-syn) impacts NfL expression, release, and functions in oligodendrocytes, as well as detect plasma NfL-positive oligodendrocyte-derived extracellular vesicles (ODEVs) changes in patients with multiple system atrophy (MSA), Parkinson's disease (PD), and healthy controls (HCs).

METHODS

NfL expression in oligodendrocytes was assessed using RNAscope and immunofluorescence staining in human and mouse brain slices, as well as flow cytometry in mouse brain single-cells. The MO3.13 oligodendrocyte cell line was used to mimic MSA pathology with α-syn overexpression or preformed fibril treatment. NfL levels were detected in cell line, brain tissues and condition media, and the differences between MSA pathology and controls were compared. Plasma NfL-positive ODEVs were quantified using nano-scale flow cytometry in a cohort of 101 MSA patients, 96 PD patients, and 97 HCs.

RESULTS

Both NEFL mRNA and NfL protein showed co-localization with typical oligodendrocyte marker anti-2,3-cyclic nucleotide-3-phosphodiesterase (CNPase). A total of 58.5% of CNPase-positive oligodendrocytes co-expressed NfL. Increased α-syn load elevates NfL expression in both oligodendrocyte cell line and MSA patient brain slices. NfL overexpression inhibited oligodendrocyte maturation, but did not affect α-syn-induced cell viability deficits. α-Syn promoted oligodendrocytic NfL release via extracellular vesicles. Plasma NfL-positive ODEVs were elevated in MSA patients compared to PD and HCs.

INTERPRETATION: These findings suggest additional cellular roles for NfL in oligodendrocytes beyond its established function in neurons and have potential implications for the neurodegenerative pathophysiology of MSA. ANN NEUROL 2025;98:1364-1379.