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<p>The triggering receptor expressed on myeloid cells 2 (<i>TREM2</i>) gene is an important risk factor in Alzheimer’s disease (AD). The signal peptide (SP) domain plays a critical role in protein secretion and localization, however, its pathogenic variant remains unclear. This study investigated the novel L15Q mutation in the <i>TREM2</i> SP domain and its effect on AD pathology. A novel <i>TREM2</i> L15Q variant was identified from a 71-year-old patient, predicting the structural and functional disruptions. To examine its impact, HEK 293 cells were transfected. Glycosylation analysis revealed a distinct doublet of immature <i>TREM2</i> bands in L15Q cells, both of which shifted upon PNGase F and Endo H treatments, confirming abnormal N-linked glycosylation. Quantifications revealed a reduced mature-to-immature ratio and decreased soluble <i>TREM2</i>, suggesting impaired protein maturation. These findings demonstrated that the L15Q mutation in the SP domain disrupted the TREM2 glycosylation, maturation and secretion. Additionally, <i>TREM2</i> L15Q cells reduced Aβ phagocytosis, elevated extracellular Aβ<sub>42</sub> and the Aβ<sub>42/40</sub> ratio, and decreased endogenous Aβ<sub>42</sub> levels, indicating the impaired Aβ clearance. Collectively, our results supported the crucial role of the <i>TREM2</i> SP domain in maintaining protein functions and Aβ homeostasis, offering new insight into <i>TREM2</i>-linked AD pathogenesis.</p>

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A novel TREM2 L15Q in signal peptide domain and its influence on Aβ pathogenicity

  • 期刊论文

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  • 发表日期：

    2026年1月23日

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  • Danyeong Kim,
  • Heewon Bae,
  • Kyu Hwan Shim,
  • Hyewon Yang,
  • Da-Eun Jeong,
  • Min Ju Kang,
  • Seong Soo A. An

摘要

The triggering receptor expressed on myeloid cells 2 (TREM2) gene is an important risk factor in Alzheimer’s disease (AD). The signal peptide (SP) domain plays a critical role in protein secretion and localization, however, its pathogenic variant remains unclear. This study investigated the novel L15Q mutation in the TREM2 SP domain and its effect on AD pathology. A novel TREM2 L15Q variant was identified from a 71-year-old patient, predicting the structural and functional disruptions. To examine its impact, HEK 293 cells were transfected. Glycosylation analysis revealed a distinct doublet of immature TREM2 bands in L15Q cells, both of which shifted upon PNGase F and Endo H treatments, confirming abnormal N-linked glycosylation. Quantifications revealed a reduced mature-to-immature ratio and decreased soluble TREM2, suggesting impaired protein maturation. These findings demonstrated that the L15Q mutation in the SP domain disrupted the TREM2 glycosylation, maturation and secretion. Additionally, TREM2 L15Q cells reduced Aβ phagocytosis, elevated extracellular Aβ42 and the Aβ42/40 ratio, and decreased endogenous Aβ42 levels, indicating the impaired Aβ clearance. Collectively, our results supported the crucial role of the TREM2 SP domain in maintaining protein functions and Aβ homeostasis, offering new insight into TREM2-linked AD pathogenesis.