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Valosin-containing protein (VCP) mutations disrupt tau splicing, leading to 4R tau accumulation and neurodegeneration in frontotemporal dementia (FTD). This 4R tau dysregulation impairs cellular functions, including endolysosomal and autophagy pathways.

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share genetic links, particularly mutations in the valosin-containing protein (VCP) gene.
  • The precise mechanisms by which VCP mutations lead to neurodegeneration are not fully understood.
  • This research explores the role of 4R tau dysregulation in cellular dysfunction within the context of VCP mutations.

Purpose of the Study:

  • To investigate how 4R tau dysregulation contributes to endolysosomal and autophagy dysfunction in human neurons with VCP mutations.
  • To determine if increased 4R tau levels can independently cause neurodegenerative phenotypes.

Main Methods:

  • Utilized human induced pluripotent stem cell (hiPSC)-derived cortical neurons carrying VCP mutations.
  • Analyzed endolysosomal integrity, RNA-binding protein (RBP) localization, and MAPT splicing.
  • Employed antisense oligonucleotides (ASOs) to manipulate 4R tau levels in control neurons and assessed cellular homeostasis via immunocytochemistry, western blotting, and proximity ligation assays.

Main Results:

  • VCP mutations led to the nuclear dissociation of FUS and SFPQ, resulting in aberrant MAPT splicing and a higher 4R tau to 3R tau ratio.
  • Neurons with VCP mutations displayed enlarged endolysosomes, lysosomal membrane rupture, impaired autophagy, endoplasmic reticulum stress, and apoptosis.
  • ASO-induced 4R tau expression in control neurons mimicked these pathological changes, confirming 4R tau as a key driver of cellular dysfunction.

Conclusions:

  • 4R tau dysregulation is a significant contributor to neurodegeneration in VCP-related FTD by disrupting endolysosomal and autophagic functions.
  • Restoring tau isoform balance presents a potential therapeutic strategy for VCP-related FTD.