An Inducible Neural Stem Progenitor Cell Model for Testing Therapeutic Interventions Against Neurodegeneration FENIB.

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a fatal neurodegenerative disease.
• Caused by mutant neuroserpin (NS) polymer accumulation in neuronal endoplasmic reticulum (ER).
• Current treatments are palliative, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To establish a novel cell culture system for FENIB drug discovery.
• To create a model for screening small molecules that reduce neuroserpin (NS) polymer formation.

Main Methods:

• Generated neural stem progenitor cells (NPCs) with inducible expression of wild-type (WT) or G392E mutant neuroserpin (NS).
• Utilized these cell lines to test four proteolysis targeting chimaera (PROTAC) compounds.
• PROTACs were designed to target mutant NS for proteasomal degradation via the E3 ubiquitin ligase cereblon.

Main Results:

• Successfully generated and characterized novel inducible NPC cell lines for FENIB modeling.
• Tested PROTAC compounds showed minimal toxicity and did not alter NS levels.
• No significant reduction in NS polymer formation was observed with the tested PROTACs.

Conclusions:

• The developed cell model provides a platform for future FENIB therapeutic research.
• This study lays the groundwork for identifying molecules that prevent ER NS accumulation.
• Further optimization of PROTACs or alternative strategies may be needed to target mutant NS degradation.