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Updated: May 18, 2026

Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis
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VCP modulation ameliorates pathological features in C9orf72 models.

Veronica Ferrari1, Barbara Tedesco1, Marta Cozzi1

  • 1Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti" (DiSFeB), Università degli Studi di Milano, Milan, Italy.

Cell Death & Disease
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Summary

Valosin-containing protein (VCP) reduces toxic C9-dipeptide repeat proteins (DPRs) in neurodegenerative disease models by enhancing protein quality control. Activating VCP with SMER28 clears DPRs and mitigates lysosomal damage, showing therapeutic potential for C9-ALS and C9-FTD.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share pathological mechanisms linked to genetic alterations like the C9ORF72 (C9) mutation.
  • The C9 mutation causes toxic dipeptide repeat proteins (DPRs) accumulation, impairing neuronal function via protein quality control (PQC) pathways, including autophagy-lysosomal degradation.
  • Valosin-containing protein (VCP) is crucial for PQC, degrading misfolded proteins and maintaining cellular homeostasis.

Purpose of the Study:

  • To investigate the role of VCP in modulating C9 mutation-associated pathology.
  • To explore VCP's mechanisms in clearing C9-DPRs and counteracting lysosomal damage.
  • To evaluate the therapeutic potential of pharmacologically activating VCP-mediated clearance using SMER28.

Main Methods:

  • Utilized neuronal cell models and induced pluripotent stem cell-derived motor neurons (iPSC-MNs) from C9-ALS mutation carriers.
  • Assessed C9-DPR levels, lysosomal function (pH, galectin-3 puncta), and autophagy-related gene expression.
  • Investigated the involvement of the ubiquitin-proteasome system (UPS) and autophagy in VCP-mediated clearance.
  • Administered SMER28 to pharmacologically activate VCP and assess its effects on C9 pathology.

Main Results:

  • VCP overexpression significantly reduced C9-DPR levels through both UPS and autophagy.
  • VCP overexpression counteracted C9-DPR-induced lysosomal damage, restoring lysosomal pH and decreasing galectin-3 puncta.
  • SMER28 treatment decreased polyGA levels in C9-iPSC-MNs, rescued differentiation commitment, and normalized autophagy-related gene expression.
  • SMER28-mediated clearance of polyPR was linked to UPS activity and mitigation of lysosomal damage.

Conclusions:

  • VCP plays a significant role in modulating C9 pathology by clearing toxic DPRs and protecting against lysosomal damage.
  • Pharmacological activation of VCP-mediated clearance using SMER28 demonstrates therapeutic potential for C9-ALS and C9-FTD.
  • Targeting VCP represents a promising therapeutic strategy for neurodegenerative diseases associated with C9ORF72 mutations.