RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• The C9orf72 gene hexanucleotide repeat expansion is the primary genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD).
• Repeat-associated non-AUG (RAN) translation produces toxic dipeptide repeat (DPR) proteins, contributing to C9ALS/FTD pathology.
• Reduced expression of AAA+ family proteins RuvBL1 and RuvBL2 is observed in C9ALS/FTD patients.

Purpose of the Study:

• To investigate the therapeutic potential of modulating RuvBL1 and RuvBL2 levels for reducing toxic DPRs in C9ALS/FTD.
• To determine the efficacy of RuvBL1 and RuvBL2 overexpression in reducing DPRs across various in vitro and in vivo models.

Main Methods:

• Assessed RuvBL1 and RuvBL2 expression levels in C9ALS/FTD patients.
• Overexpressed RuvBL1 and RuvBL2 in cell lines, primary neurons, and patient-derived iPSC motor neurons to quantify DPR levels.
• Evaluated the in vivo effects of RuvBL2 overexpression on DPR-related motor phenotypes in a Drosophila model.

Main Results:

• C9ALS/FTD patients exhibit decreased RuvBL1 and RuvBL2 expression.
• Overexpression of RuvBL1 and, more significantly, RuvBL2 reduced DPR levels in diverse in vitro models.
• RuvBL2 overexpression in a Drosophila model ameliorated DPR-induced motor deficits.

Conclusions:

• Modulating RuvBL protein levels, particularly RuvBL2, offers a promising therapeutic avenue for C9ALS/FTD by reducing toxic DPR accumulation.
• RuvBL1 and RuvBL2 play a crucial role in clearing DPRs, and their augmentation could mitigate C9ALS/FTD progression.