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Updated: Jun 3, 2025

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Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of

Vicente Valenzuela1, Daniela Becerra1, José I Astorga1

  • 1Program of Cellular and Molecular Biology, Biomedical Sciences Institute (ICBM), Universidad de Chile, Santiago, Chile; Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile; FONDAP Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|January 12, 2025
PubMed

Insights

Restoring endoplasmic reticulum (ER) proteostasis by enhancing the unfolded protein response (UPR) with XBP1s shows promise for treating amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This approach improved motor function and survival in disease models.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic causes and pathological features, including protein aggregation.
  • Impaired endoplasmic reticulum (ER) proteostasis and suboptimal activation of the unfolded protein response (UPR) are common underlying mechanisms in ALS and FTD.
  • The transcription factor X-box binding protein 1 spliced (XBP1s) is a key regulator of the UPR, crucial for managing ER stress.

Purpose of the Study:

  • To investigate whether artificially enhancing the UPR via XBP1s expression can ameliorate ALS and FTD pathology.
  • To evaluate the therapeutic potential of targeting ER proteostasis as a pan-therapeutic strategy for ALS/FTD spectrum disorders.

Main Methods:

  • Adeno-associated viruses (AAVs) were used to deliver the gene for active XBP1s into the nervous systems of established ALS and FTD animal models.
  • Motor performance, lifespan, protein aggregation, and proteomic profiles of spinal cord tissue were assessed in treated and control animals.
  • Experimental ER stress was induced to evaluate UPR activation levels in disease models.

Main Results:

  • Intracerebroventricular administration of AAV-XBP1s improved motor function and extended lifespan in mutant SOD1 mice, accompanied by reduced protein aggregation.
  • AAV-XBP1s treatment attenuated disease progression in models associated with TDP-43 and C9orf72 mutations, key genetic drivers of ALS/FTD.
  • Proteomic analysis revealed that XBP1s overexpression enhanced proteostasis and modulated synaptic and cell morphology proteins in the spinal cord.

Conclusions:

  • Enhancing ER proteostasis through UPR activation by XBP1s represents a viable therapeutic strategy for ALS and FTD.
  • Targeting the UPR offers a potential pan-therapeutic approach for the diverse spectrum of ALS/FTD diseases.
  • Restoring proteostasis via XBP1s may counteract the detrimental effects of protein misfolding and aggregation in neurodegeneration.
Keywords:
ER stressXBP1amyotrophic lateral sclerosisfrontotemporal dementiagene therapyprotein aggregationunfolded protein response

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