Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• The C9orf72 hexanucleotide repeat expansion (G4C2) is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Currently, no targeted therapies exist for C9orf72-associated ALS and FTD.
• Understanding the molecular mechanisms driving neurodegeneration in these conditions is critical for therapeutic development.

Purpose of the Study:

• To investigate the pathogenic mechanisms underlying C9orf72-associated ALS/FTD.
• To identify potential therapeutic targets for C9orf72-mediated neurodegeneration.

Main Methods:

• Utilized induced pluripotent stem cell (iPSC)-derived post-mitotic neurons from C9orf72 carriers.
• Analyzed cell-cycle progression, protein expression (cyclins, CDKs), and effects of dipeptide repeat proteins (poly-GR, poly-PR).
• Administered the FDA-approved CDK4/6 inhibitor palbociclib and performed single-nucleus RNA sequencing on patient cortical samples.

Main Results:

• C9orf72 carrier neurons showed age-dependent cell-cycle reentry, increased S-phase entry, and elevated cyclin/CDK expression.
• Arginine-containing dipeptide repeat proteins (poly-GR, poly-PR) activated CDK4/6, driving aberrant cell-cycle progression.
• Palbociclib treatment normalized cell-cycle progression, reduced motor neuron death, and restored synaptic proteins.
• Patient cortical samples confirmed cell-cycle activation and alterations in related pathways.

Conclusions:

• Cell-cycle dysregulation is a key pathogenic mechanism in C9orf72 ALS/FTD.
• CDK4/6 signaling is implicated in the disease pathogenesis.
• Targeting CDK4/6 with inhibitors like palbociclib represents a promising therapeutic strategy for C9orf72-associated neurodegenerative diseases.