Objective: This research investigated the active pathogenic property of Neurofilament light chain (NfL) in contributing to PD-like pathophysiology. We aimed to elucidate these mechanisms by benchmarking the neurotoxic effects of NfL, comparing with the classical 6-hydroxydopamine-induced PD model.

Background: NfL is widely utilised as a passive fluid biomarker indicative of axonal injury across neurodegenerative disorders, notably Parkinson’s disease (PD). Despite its clinical applicability, the functional and potentially neurotoxic effects of extracellular NfL aggregates remain largely uncharacterised.

Method: We characterised and validated the fibrillar morphology and aggregation state of the NfL proteins using atomic force microscopy (AFM), prior to in vivo administration. Following the NfL injection, longitudinal behavioural phenotyping was checked on days 0, 14, and 28 post-injection. This included evaluating various motor coordination tests and cognitive memory using the novel object recognition test (NORT). At the 28 dpi, we quantified neuropathological hallmarks, including oxidative stress, apoptotic, and proinflammatory mediators, alongside neuronal survival (NeuN), synaptic integrity (DAT), and reactive gliosis (GFAP and IBA-1). We also analysed the co-localisation of tyrosine hydroxylase (TH) with pathological α-synuclein aggregation, which correlates with dopaminergic deterioration in the substantia nigra pars compacta (SNpc) and the striatum (STR).

Results: In vivo NfL administration precipitated severe motor coordination deficits, cognitive decline, and anxiety-like behaviours, mirroring 6-OHDA pathology. We found that NfL exposure drove a stark downregulation of dopaminergic markers, including TH and DAT, alongside a loss of NeuN expression at the molecular level in the SNpc and STR. This neurodegeneration was paralleled by a robust buildup of α-synuclein. Furthermore, extracellular NfL disrupted redox homeostasis and triggered a dose-dependent exacerbation of neuroinflammation and reactive gliosis.

Conclusion: These findings provide the first in vivo evidence that extracellular NfL aggregates not only contribute to neuroinflammation but also actively precipitate dopaminergic neurodegeneration and cognitive impairment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neurofilament-light-chain-triggers-protein-aggregation-neurotoxicity-and-gliosis-in-parkinsons-disease-through-p38-mk2-nf-%ce%bab-creb1-and-nrf2-ho-1-signalling/