Breakdown of the central synapses in C9orf72-linked ALS/FTD

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons, with limited treatment options.
• Cortical hyper-excitability is an early, pre-symptomatic feature of ALS, preceding motor neuron degeneration.
• The C9ORF72 gene mutation, a repeat expansion (GGGGCC)n, links ALS and frontotemporal dementia (FTD) as a disease spectrum.

Purpose of the Study:

• To review synaptic dysfunctions in the central nervous system associated with the C9ORF72 repeat expansion.
• To explore the role of C9ORF72 in maintaining synaptic physiology.
• To understand how C9ORF72 mutations contribute to ALS and FTD pathogenesis.

Main Methods:

• Literature review of studies on C9ORF72 repeat expansion in ALS and FTD.
• Analysis of findings from patient data, organismal models, and cellular models.
• Synthesis of evidence regarding synaptic dysfunction mechanisms.

Main Results:

• The C9ORF72 repeat expansion is linked to synaptic dysfunction in both ALS and FTD.
• Synaptic dysfunction occurs early in the disease process and is a common feature.
• C9ORF72 gene products appear critical for normal synaptic function.

Conclusions:

• Synaptic dysfunction is a key pathological mechanism in C9ORF72-associated ALS and FTD.
• Targeting synaptic pathways may offer therapeutic strategies for these diseases.
• Further research into C9ORF72's synaptic roles is crucial for understanding ALS/FTD spectrum disorders.