{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNEFH—particularly in its phosphorylated form (pNF‐H)—has emerged as a critical biomarker of axonal integrity across a range of neurologic conditions. Studies have demonstrated that levels of pNF‐H (and related neurofilament subunits) in cerebrospinal fluid, blood, and other body fluids correlate with axonal injury in amyotrophic lateral sclerosis, traumatic brain injury, stroke, frontotemporal dementia, and multiple sclerosis. These investigations support the use of NEFH measurements for early diagnosis, prognosis, monitoring disease progression, and even therapeutic evaluation, as higher pNF‐H levels tend to indicate more severe neurodegeneration and poorer clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role as a biomarker, NEFH functions as a key component of the neuronal cytoskeleton, contributing to the maintenance of axonal caliber and structural stability. Under physiological conditions NEFH is extensively phosphorylated—a modification regulated in part by kinases such as GSK3β and modulatory factors like Pin1—which maintains proper filament assembly and spacing. Conversely, aberrant hyperphosphorylation and misregulation of NEFH have been linked to pathological protein aggregation in neurodegenerative disorders, and alterations in NEFH expression (often mediated via promoter methylation) have been implicated in activating pathways (e.g. Akt/β‐catenin) that may contribute to tumorigenesis in cancers such as esophageal and renal cell carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic alterations in NEFH further underscore its central role in neuronal health. Rare coding variants, including missense changes and frameshift mutations that lead to aberrant C‐terminal amino acid sequences, have been linked to motor neuron disease phenotypes and axonal neuropathies such as Charcot–Marie–Tooth disease. In addition, common NEFH polymorphisms (for example, genotypes differing in the number of tail domain repeat motifs) have been associated with sporadic motor neuron disease and even alterations in cytoarchitecture in disorders like schizophrenia, suggesting that both structural disruption and dysregulated NEFH expression may contribute to disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yolande A L Pijnenburg, John C Janssen, Niki S M Schoonenboom, et al. 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