Basic Science and Pathogenesis

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.