Scholarlink

<p>A hallmark of Alzheimer’s disease (AD) is the accumulation of extracellular amyloid-β plaques in the brain. Amyloid-β is a 40–42 amino acid peptide generated by proteolytic processing of amyloid precursor protein (APP) via membrane-bound proteases. APP is a transmembrane protein, and its trafficking to sites of proteolysis represents a rate-limiting step in AD progression. Although APP processing has been well-studied, its trafficking itinerary and machinery remain incompletely understood. To address this, we performed an unbiased interaction screen for interactors of the APP cytosolic tail. We identified previously characterised APP binders as well as novel interactors, including RABGAP1. We demonstrated that RABGAP1 partially co-localises with APP and directly interacts with a YENPTY motif in the APP cytosolic tail. Depletion or overexpression of RABGAP1 caused mistrafficking and misprocessing of endogenous APP in human and rodent neurons. This effect is dependent on the GAP activity of RABGAP1, demonstrating that RABGAP1 affects the trafficking of APP by modulating RAB activity on endosomal subdomains. This novel trafficking mechanism has implications for other NPXY cargoes and presents a possible therapeutic avenue to explore.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

RABGAP1 is a sensor that facilitates the sorting and processing of amyloid precursor protein

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月26日

查看全文
  • Jessica Eden,
  • Jonathan G G Kaufman,
  • Conceição Pereira,
  • Eleanor Fox,
  • Jerome Cattin-Ortolá,
  • Lorena Benedetti,
  • Bart Nieuwenhuis,
  • David J Owen,
  • Jennifer Lippincott-Schwartz,
  • Sean Munro,
  • David C Gershlick

摘要

A hallmark of Alzheimer’s disease (AD) is the accumulation of extracellular amyloid-β plaques in the brain. Amyloid-β is a 40–42 amino acid peptide generated by proteolytic processing of amyloid precursor protein (APP) via membrane-bound proteases. APP is a transmembrane protein, and its trafficking to sites of proteolysis represents a rate-limiting step in AD progression. Although APP processing has been well-studied, its trafficking itinerary and machinery remain incompletely understood. To address this, we performed an unbiased interaction screen for interactors of the APP cytosolic tail. We identified previously characterised APP binders as well as novel interactors, including RABGAP1. We demonstrated that RABGAP1 partially co-localises with APP and directly interacts with a YENPTY motif in the APP cytosolic tail. Depletion or overexpression of RABGAP1 caused mistrafficking and misprocessing of endogenous APP in human and rodent neurons. This effect is dependent on the GAP activity of RABGAP1, demonstrating that RABGAP1 affects the trafficking of APP by modulating RAB activity on endosomal subdomains. This novel trafficking mechanism has implications for other NPXY cargoes and presents a possible therapeutic avenue to explore.