The unfolded protein response: mechanisms and therapy of neurodegeneration

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Protein-misfolding diseases share a common theme: activation of the unfolded protein response (UPR).
• UPR activation is observed in patient tissues and animal models of neurodegeneration.
• Evidence suggests UPR activation is an active contributor to disease, not just a consequence.

Purpose of the Study:

• To investigate the role of the protein kinase RNA-like ER kinase (PERK) pathway in neurodegenerative disease pathogenesis.
• To determine if pharmacological inhibition of PERK signaling can prevent neurodegeneration and disease progression.
• To explore the potential of targeting the UPR as a generic therapeutic strategy for neurodegenerative disorders.

Main Methods:

• Utilized genetic and pharmacological manipulation of the UPR pathway in mouse models of neurodegenerative disease.
• Assessed the impact of PERK pathway modulation on neuronal protein synthesis rates.
• Evaluated the neuroprotective effects and disease prevention capabilities of small molecule inhibitors in vivo.

Main Results:

• Overactivation of the PERK (EIF2AK3) branch of the UPR directly contributes to neurodegeneration by reducing neuronal protein synthesis.
• Pharmacological inhibition of the PERK pathway demonstrated significant neuroprotection in disease models.
• The first small molecule shown to prevent neurodegeneration and clinical disease in vivo was discovered.

Conclusions:

• Targeting the PERK-mediated translational failure within the UPR is a promising therapeutic strategy for dementia and neurodegenerative diseases.
• This approach offers a potential generic treatment for a spectrum of neurodegenerative disorders, independent of specific disease proteins.
• Pharmacological inhibition of the PERK pathway represents a novel therapeutic avenue for boosting memory and preventing neurodegeneration.