Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron degeneration.
• Synaptic integrity defects occur early in ALS pathogenesis, preceding neuronal loss.
• The underlying mechanisms of early synaptic dysfunction in ALS remain poorly understood.

Purpose of the Study:

• To investigate early synaptic defects in Amyotrophic Lateral Sclerosis (ALS) using a motor neuron model.
• To explore the role of Fused in Sarcoma (FUS) protein aggregation in synaptic pathology.
• To evaluate the therapeutic potential of modulating autophagy in an ALS context.

Main Methods:

• Expression of an ALS-linked FUS variant in adult motor neurons.
• Assessment of synaptic pathology at the neuromuscular junction (NMJ).
• Modulation of autophagy through Rab1, FMR1 expression, or Rapamycin treatment.

Main Results:

• Accumulation of FUS-positive aggregates observed at synaptic terminals.
• Reduced microtubule stability associated with FUS aggregation.
• Autophagy induction via Rab1, FMR1, or Rapamycin decreased aggregate formation.
• Restoration of synaptic structure and function was achieved through autophagy induction.

Conclusions:

• Early synaptic dysfunction in ALS is linked to FUS aggregation and microtubule instability.
• Inducing autophagy is a viable strategy to mitigate early synaptic defects in ALS.
• Targeting autophagy presents a potential therapeutic avenue for preventing advanced ALS progression.