Neurofilament light chain protein exposure contributes to protein aggregation, microgliosis, astrogliosis and neuroinflammation via p38/MK2/NF-κB/CREB1/Nrf2/HO-1 signalling leading to Parkinson's disease.

Abstract

The neurofilament light chain (NfL) is a well-established biomarker specific to neuronal structural integrity across various neurodegenerative conditions, including Parkinson's disease. (PD). This research investigated how the NfL protein may actively contribute to PD progression by comparing its effects with those of the 6-hydroxydopamine (6-OHDA)-induced mouse model. Atomic force microscopy (AFM) was used to characterise NfL aggregation and fibril morphology before injection. We monitored movement, coordination, and cognitive abilities in animals on days 0, 14, and 28 following injections. We evaluated various molecular biochemical changes, including the expression of the proinflammatory and apoptotic proteins, expression of dopamine transporter (DAT), neuronal nuclear marker (NeuN) and gliosis markers (GFAP and IBA-1) and colocalization of tyrosine hydroxylase (TH) and α-synuclein accumulation to simultaneously assess hallmarks of dopaminergic pathology in the striatum and substantia nigra pars compacta (SNpc) regions of the brain on day 28 post-surgery. NfL exposure led to a significant change in movement, induction of anxiety-like symptoms, and reduced cognitive behaviours. We found a marked reduction in the levels of TH, accompanied by an increased α-synuclein accumulation. We also observed a reduction in dopamine transporter (DAT) and neuronal nuclear antigen (NeuN) expression in both these regions. Furthermore, NfL exposure impaired oxidative balance, activated proinflammatory biomarkers and gliosis in a dose-dependent manner. This study has provided a direct evidence on the pathological role of NfL exposure and its aggregation in vivo, offering new mechanistic insights into NfL-induced PD progression in animals.