Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• The GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Pathogenesis involves both gain-of-function (GOF) from dipeptide repeat proteins (DPRs) and loss-of-function (LOF) of C9ORF72.
• DPRs cause ribosomal dysfunction, nucleolar stress, and impaired proteostasis, while C9ORF72 LOF affects microglial lysosomal and autophagic pathways, disrupting immune homeostasis.

Purpose of the Study:

• To review current knowledge on DPR biology and microglial dysfunction in C9ORF72-associated ALS/FTD.
• To discuss therapeutic strategies targeting RNA, DPRs, proteostasis, autophagy, and neuroinflammation.
• To highlight the potential of fluid biomarkers for diagnosis and monitoring.

Main Methods:

• Literature review synthesizing current research on C9ORF72-associated neurodegenerative diseases.
• Analysis of molecular mechanisms including repeat-associated non-AUG (RAN) translation and its consequences.
• Evaluation of emerging therapeutic targets and fluid biomarkers.

Main Results:

• DPRs disrupt cellular processes leading to neuronal injury and neurodegeneration.
• Microglial dysfunction and chronic neuroinflammation are key contributors to disease progression.
• Fluid biomarkers like CSF poly (GP) and blood NfL show promise for clinical applications.

Conclusions:

• Understanding DPR biology and microglial roles is crucial for C9ORF72-associated ALS/FTD.
• Targeting multiple pathways offers potential therapeutic avenues.
• Fluid biomarkers can aid in diagnosis, monitoring, and assessing treatment efficacy.