Preliminary Characterization of Molecular Changes in iPSC-based Huntington's Disease Models Following psPEF Exposure
Poster #: 119
Session/Time: B
Author:
Mackenzie Anne Tardif-Kunk, BS
Mentor:
Peter A. Mollica, PhD
Research Type: Basic Science
Abstract
INTRODUCTION:
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive motor and cognitive impairments. It is caused by an unstable expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene, often exceeding 35-40 repeats. The resultant extended polyglutamine tract in mutant huntingtin (mHTT) disrupts normal protein folding and leads to pathogenic intracellular protein aggregates. In our previous work, we proposed picosecond pulsed electric fields (psPEF) as a means to dissolve mHTT aggregates and demonstrated proof of concept in human neuronal stem cells (NSCs) derived from HD patients via induced pluripotency. Here, we examine the downstream effects of psPEF following aggregate disruption.
METHODS:
HD-NSCs were exposed to psPEF at 20 kV/cm or 40 kV/cm stimuli using a modified 3D bioprinter. Expression of neural gene was determined by qPCR. Mitochondrial membrane potential (DYm) was measured by tetramethylrhodamine ethyl ester (TMRE) staining.
RESULTS:
Although a single exposure did not produce significant changes, preliminary data revealed dose-dependent increases in the expression of several neural genes often suppressed in HD, including BDNF, DRD2, mGluR1, GABARAP, SYN1, and DCX. Additionally, mitochondrial membrane potential-known to be compromised in HD-was restored in a dose-dependent manner.
CONCLUSION:
While these findings are based on in vitro data, they highlight the potential of psPEF to modulate mHTT pathology and warrant further investigation, including in vivo validation, as current HD treatments are primarily limited to symptom management.
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive motor and cognitive impairments. It is caused by an unstable expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene, often exceeding 35-40 repeats. The resultant extended polyglutamine tract in mutant huntingtin (mHTT) disrupts normal protein folding and leads to pathogenic intracellular protein aggregates. In our previous work, we proposed picosecond pulsed electric fields (psPEF) as a means to dissolve mHTT aggregates and demonstrated proof of concept in human neuronal stem cells (NSCs) derived from HD patients via induced pluripotency. Here, we examine the downstream effects of psPEF following aggregate disruption.
METHODS:
HD-NSCs were exposed to psPEF at 20 kV/cm or 40 kV/cm stimuli using a modified 3D bioprinter. Expression of neural gene was determined by qPCR. Mitochondrial membrane potential (DYm) was measured by tetramethylrhodamine ethyl ester (TMRE) staining.
RESULTS:
Although a single exposure did not produce significant changes, preliminary data revealed dose-dependent increases in the expression of several neural genes often suppressed in HD, including BDNF, DRD2, mGluR1, GABARAP, SYN1, and DCX. Additionally, mitochondrial membrane potential-known to be compromised in HD-was restored in a dose-dependent manner.
CONCLUSION:
While these findings are based on in vitro data, they highlight the potential of psPEF to modulate mHTT pathology and warrant further investigation, including in vivo validation, as current HD treatments are primarily limited to symptom management.