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<p>Huntington disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion (polyQ) in the Huntingtin protein (muHTT), which makes it prone to misfolding and aggregation. muHTT aggregates sequester a wide variety of proteins essential for cell homeostasis, including chaperones and transcription factors, and their depletion may contribute to HD pathogenesis. Lysosomes are the main hubs for degradative and signaling activities in cells, and their functionality is crucial for cell homeostasis, especially for neurons. Different forms of cellular stresses, including proteotoxic stresses, can alter lysosome integrity and induce lysosomal membrane permeabilization (LMP). Damaged lysosomes are recognized by galectins, in particular galectin-3 (LGALS3) with activation of the lysosome quality control (LQC) system responsible for repairing, degrading, or replacing leaky lysosomes. The system is transcriptionally regulated by the transcription factors EB and E3 (TFEB and TFE3, respectively). Using HD mouse and cell models, we demonstrated that TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events. Moreover, we demonstrated that <i>TFEB</i> and <i>TFE3</i> silencing or overexpression modulate muHTT aggregation. TFEB and TFE3 knockdown worsens muHTT aggregation, while their overexpression reduces muHTT inclusions and concurrently reduces LGALS3 accumulation via lysophagy and lysosome replacement. Our findings suggest that both TFEB and TFE3 are implicated in HD, and their sequestration in muHTT inclusions increase the vulnerability of neurons to lysosome injury, altering LQC and contributing to disease pathogenesis.</p><p></p>

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Impairment of lysosomal quality control in Huntington disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月27日

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  • Paola Rusmini,
  • Francesco Mina,
  • Marta Valenza,
  • Martina Vitali,
  • Veronica Ferrari,
  • Barbara Tedesco,
  • Elena Casarotto,
  • Marta Cozzi,
  • Marta Chierichetti,
  • Ali Mohamed,
  • Paola Pramaggiore,
  • Laura Cornaggia,
  • Carmelo Milioto,
  • Maria Brodnanova,
  • Rocio Magdalena,
  • Prashant Koshal,
  • Margherita Piccolella,
  • Riccardo Cristofani,
  • Mariarita Galbiati,
  • Valeria Crippa,
  • Angelo Poletti

摘要

Huntington disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion (polyQ) in the Huntingtin protein (muHTT), which makes it prone to misfolding and aggregation. muHTT aggregates sequester a wide variety of proteins essential for cell homeostasis, including chaperones and transcription factors, and their depletion may contribute to HD pathogenesis. Lysosomes are the main hubs for degradative and signaling activities in cells, and their functionality is crucial for cell homeostasis, especially for neurons. Different forms of cellular stresses, including proteotoxic stresses, can alter lysosome integrity and induce lysosomal membrane permeabilization (LMP). Damaged lysosomes are recognized by galectins, in particular galectin-3 (LGALS3) with activation of the lysosome quality control (LQC) system responsible for repairing, degrading, or replacing leaky lysosomes. The system is transcriptionally regulated by the transcription factors EB and E3 (TFEB and TFE3, respectively). Using HD mouse and cell models, we demonstrated that TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events. Moreover, we demonstrated that TFEB and TFE3 silencing or overexpression modulate muHTT aggregation. TFEB and TFE3 knockdown worsens muHTT aggregation, while their overexpression reduces muHTT inclusions and concurrently reduces LGALS3 accumulation via lysophagy and lysosome replacement. Our findings suggest that both TFEB and TFE3 are implicated in HD, and their sequestration in muHTT inclusions increase the vulnerability of neurons to lysosome injury, altering LQC and contributing to disease pathogenesis.