Targeted stabilization of Munc18-1 function via pharmacological chaperones

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Heterozygous de novo mutations in Munc18-1 cause severe neurodevelopmental disorders like epilepsy and intellectual disability.
• Current treatments lack disease-modifying effects; chemical chaperones show limited efficacy due to high concentrations and toxicity.
• Munc18-1 dysfunction arises from protein aggregation, reducing functional levels and impairing neurotransmitter release.

Purpose of the Study:

• To identify and develop a targeted therapy for Munc18-1-related pediatric encephalopathies.
• To find pharmacological chaperones that can bind and correct Munc18-1 aggregation and dysfunction.

Main Methods:

• Employed structure-based drug design to identify novel pharmacological chaperones.
• Tested chaperone efficacy in vitro and in vivo models of Munc18-1-related disorders.
• Assessed the impact of chaperones on Munc18-1 aggregation and neuronal function.

Main Results:

• Identified two novel pharmacological chaperones that bind to both wild-type and mutant Munc18-1.
• Demonstrated that these chaperones revert Munc18-1 aggregation in vitro and in vivo.
• Showed restoration of neuronal function, alleviating Munc18-1-related dysfunction.

Conclusions:

• The identified pharmacological chaperones represent the first targeted treatment strategy for Munc18-1-related pediatric encephalopathies.
• This approach offers a promising avenue for disease modification in these severe neurological disorders.