Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-03-07 DOI:10.1016/j.celrep.2025.115382

Olga I Kahn, Sara L Dominguez, Caspar Glock, Margaret Hayne, Steve Vito, Arundhati Sengupta Ghosh, Max Adrian, Braydon L Burgess, William J Meilandt, Brad A Friedman, Casper C Hoogenraad

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引用次数: 0

Abstract

Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracellular space following neuronal injury. While NfL has been extensively studied as a disease biomarker, the underlying release mechanisms and role in neurodegeneration remain poorly understood. Here, we find that neurons secrete low baseline levels of NfL, while neuronal damage triggers calpain-driven proteolysis and release of fragmented NfL. Secreted NfL activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize in vivo single-cell RNA sequencing to profile brain cells after injection of recombinant NfL into the mouse hippocampus and find robust macrophage and microglial responses. Consistently, NfL knockout mice ameliorate microgliosis and delay symptom onset in the SOD1 mouse model of amyotrophic lateral sclerosis (ALS). Our results show that released NfL can activate myeloid cells in the brain and is, thus, a potential therapeutic target for neurodegenerative diseases.

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神经丝蛋白轻链（NfL）是一种神经元特异性细胞骨架蛋白，为轴突提供结构支持，并在神经元损伤后释放到细胞外空间。虽然 NfL 作为一种疾病生物标志物已被广泛研究，但人们对其潜在的释放机制和在神经变性中的作用仍然知之甚少。在这里，我们发现神经元分泌的 NfL 基线水平较低，而神经元损伤会触发钙蛋白酶驱动的蛋白水解并释放碎片化的 NfL。分泌的NfL可激活小神经胶质细胞，而抗NfL抗体可阻断小神经胶质细胞的激活。我们利用体内单细胞RNA测序技术对小鼠海马注射重组NfL后的脑细胞进行了分析，发现巨噬细胞和小神经胶质细胞反应强烈。同样，在肌萎缩性脊髓侧索硬化症（ALS）的 SOD1 小鼠模型中，NfL 基因敲除小鼠可改善小胶质细胞病变并延迟症状的出现。我们的研究结果表明，释放的 NfL 能激活大脑中的髓细胞，因此是神经退行性疾病的潜在治疗靶点。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.