HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene.
• The peripheral innate immune system plays a role in HD pathogenesis, but the mechanisms linking mutant huntingtin in immune cells to disease are unclear.

Purpose of the Study:

• To investigate the cell-intrinsic effects of mutant huntingtin expression in human myeloid cells.
• To explore the potential of small interfering RNA (siRNA) delivery to lower huntingtin expression and reverse disease-associated cellular dysfunction in HD.

Main Methods:

• Analysis of cytokine production and NFκB pathway activation in myeloid cells from HD patients.
• Utilized glucan-encapsulated siRNA particles for targeted huntingtin lowering in primary human HD monocytes/macrophages.

Main Results:

• Human HD myeloid cells exhibit excessive inflammatory cytokine production due to mutant huntingtin's cell-intrinsic effects.
• Mutant huntingtin directly impacts the NFκB pathway, leading to increased RelA translocation and altered immune signaling.
• siRNA-mediated huntingtin lowering reversed elevated cytokine production and transcriptional changes in HD cells.

Conclusions:

• Mutant huntingtin expression in immune cells directly drives inflammatory responses relevant to Huntington's disease.
• Glucan-encapsulated siRNA particles represent a novel tool for studying HD pathogenesis ex vivo and offer a potential therapeutic strategy for immune cell-directed huntingtin lowering.