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<p>Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular <i>vesicles</i>, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (<i>n</i> = 21) and healthy controls (<i>n</i> = 16), and quantified exosomal HERV-K <i>gag</i>, <i>env</i>, and <i>pol</i> transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K <i>pol</i> expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (<i>P</i> = 0.037–0.051). <i>env</i> and <i>gag</i> also showed increased expression, though with greater variability. Normalization to the exosome-specific gene <i>SOD2</i> provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly <i>pol</i>, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K–targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.</p>

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Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Triparna Roy,
  • Misha Ramesh,
  • Nurul Aisha Ahmad Nizam,
  • Steven Tandiono,
  • Khuloud T. Al-Jamal,
  • Ammar Al-Chalabi,
  • Alfredo Iacoangeli,
  • Ahmad Al Khleifat

摘要

Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n = 21) and healthy controls (n = 16), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P = 0.037–0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K–targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.