{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeurofilament medium (NEFM), a principal component of the neuronal intermediate filament network, is essential for maintaining axonal structure and integrity. Recent studies have revealed that NEFM is subject to dynamic post‐translational modifications – notably O‑GlcNAc glycosylation and extensive phosphorylation – which regulate its assembly and axonal distribution. In human neurons, NEFM tail domain glycosylation has been shown to be closely interwoven with phosphorylation cascades, with shifts in modification status correlating with changes in axonal localization, while computational models suggest that the projection domains of NEFM contribute to the electrostatic organization of the neurofilament corona. Moreover, in Alzheimer’s disease, NEFM becomes aberrantly hyperphosphorylated and its increased levels may contribute to the formation of pathological aggregates, with additional evidence implicating regulatory protein partners such as spinophilin in modulating its phosphorylation status."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in NEFM expression and genetic variants have been associated with a spectrum of neurodegenerative and neuropsychiatric disorders. Mutation analyses have identified rare NEFM variants in patients with Parkinson’s disease and suggested that, although these alterations do not overtly disrupt filament assembly, they may still contribute to disease susceptibility. Similarly, in amyotrophic lateral sclerosis (ALS), aberrant regulation of NEFM transcript levels—potentially driven by dysregulated microRNA networks—can disturb the precise stoichiometry of neurofilament subunits and favor the formation of cytoplasmic inclusions. In addition, autoantibodies targeting NEFM have been detected in subgroups of patients with schizophrenia, and genetic variations in the gene encoding NEFM (NEF3) have been correlated with differential responses to antipsychotic treatment. Emerging evidence from studies evaluating cerebrospinal fluid markers further supports a role for NEFM as a marker of neurodegenerative processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its structural role in neurons, NEFM also appears to function in non‐canonical settings. In aldosterone-producing adenomas, NEFM is selectively expressed in zona glomerulosa-like cells and acts as a negative regulator of aldosterone secretion and cell proliferation. Mechanistically, NEFM interacts with dopamine D1 receptors to facilitate their internalization, thereby modulating dopaminergic signaling that influences both hormonal release and cell growth. In addition, alterations in NEFM DNA methylation have been linked to changes in immune infiltration and prognosis in breast cancer, suggesting that its regulatory functions may extend to tumor biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yipeng Wang, Qun Wang, Jianzhi Wang "}, {"type": "b", "children": [{"type": "t", "text": "[Detection of level and mutation of neurofilament mRNA in Alzheimer's disease]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhonghua Yi Xue Za Zhi (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12133495"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12133495"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Nina Lüdemann, Albrecht Clement, Volkmar H Hans, et al. "}, {"type": "b", "children": [{"type": "t", "text": "O-glycosylation of the tail domain of neurofilament protein M in human neurons and in spinal cord tissue of a rat model of amyotrophic lateral sclerosis (ALS)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M504395200"}], "href": "https://doi.org/10.1074/jbc.M504395200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16006557"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16006557"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "F A M Leermakers, E B Zhulina "}, {"type": "b", "children": [{"type": "t", "text": "How the projection domains of NF-L and alpha-internexin determine the conformations of NF-M and NF-H in neurofilaments."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Biophys J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00249-010-0585-z"}], "href": "https://doi.org/10.1007/s00249-010-0585-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20213320"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20213320"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Parvathi Rudrabhatla, Philip Grant, Howard Jaffe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Quantitative phosphoproteomic analysis of neuronal intermediate filament proteins (NF-M/H) in Alzheimer's disease by iTRAQ."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.10-157859"}], "href": "https://doi.org/10.1096/fj.10-157859"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20624930"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20624930"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Andrew C Hiday, Michael C Edler, Asma B Salek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neural Plast (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2017/4153076"}], "href": "https://doi.org/10.1155/2017/4153076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28634551"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28634551"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Rejko Krüger, Christian Fischer, Thorsten Schulte, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation analysis of the neurofilament M gene in Parkinson's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Lett (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0304-3940(03)00903-0"}], "href": "https://doi.org/10.1016/s0304-3940(03"}, {"type": "t", "text": "00903-0) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14583397"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14583397"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Raul Perez-Olle, Miguel A Lopez-Toledano, Ronald K H Liem "}, {"type": "b", "children": [{"type": "t", "text": "The G336S variant in the human neurofilament-M gene does not affect its assembly or distribution: importance of the functional analysis of neurofilament variants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuropathol Exp Neurol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jnen/63.7.759"}], "href": "https://doi.org/10.1093/jnen/63.7.759"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15290901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15290901"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Rael D Strous, Lior Greenbaum, Kyra Kanyas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of the dopamine receptor interacting protein gene, NEF3, with early response to antipsychotic medication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Neuropsychopharmacol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1017/S1461145706006651"}], "href": "https://doi.org/10.1017/S1461145706006651"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16734940"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16734940"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Amanda L Jones, Bryan J Mowry, Duncan E McLean, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated levels of autoantibodies targeting the M1 muscarinic acetylcholine receptor and neurofilament medium in sera from subgroups of patients with schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroimmunol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jneuroim.2014.02.008"}], "href": "https://doi.org/10.1016/j.jneuroim.2014.02.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24636402"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24636402"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Danae Campos-Melo, Zachary C E Hawley, Michael J Strong "}, {"type": "b", "children": [{"type": "t", "text": "Dysregulation of human NEFM and NEFH mRNA stability by ALS-linked miRNAs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Brain (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13041-018-0386-3"}], "href": "https://doi.org/10.1186/s13041-018-0386-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30029677"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30029677"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kimon Runge, Agnes Balla, Bernd L Fiebich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neurodegeneration Markers in the Cerebrospinal Fluid of 100 Patients with Schizophrenia Spectrum Disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Schizophr Bull (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/schbul/sbac135"}], "href": "https://doi.org/10.1093/schbul/sbac135"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36200879"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36200879"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Carmela Maniero, Sumedha Garg, Wanfeng Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)-Mediated Secretion of Aldosterone."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hypertension (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/HYPERTENSIONAHA.117.09231"}], "href": "https://doi.org/10.1161/HYPERTENSIONAHA.117.09231"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28584012"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28584012"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Dandan Li, Wenhao Zhao, Xinyu Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEFM DNA methylation correlates with immune infiltration and survival in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Epigenetics (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13148-021-01096-4"}], "href": "https://doi.org/10.1186/s13148-021-01096-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34001208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34001208"}]}]}]}