Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) involves neuromuscular junction (NMJ) disruption and neurodegeneration.
• TAR DNA-binding protein 43 (TDP-43) accumulation in axons contributes to NMJ disruption by inhibiting local protein synthesis.
• The mechanisms driving TDP-43 axonal accumulation are not fully understood.

Purpose of the Study:

• To investigate the mechanisms underlying TDP-43 axonal accumulation in Amyotrophic lateral sclerosis (ALS).
• To identify the role of muscle-derived factors in regulating TDP-43 localization and its impact on neuromuscular junctions (NMJs).

Main Methods:

• Analysis of TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice.
• Investigating the role of muscle-derived miR-126a-5p extracellular vesicles (EVs) in regulating TDP-43 synthesis.
• Assessing the neuroprotective effects of miR-126 in SOD1^G93A mice and co-culture models.

Main Results:

• TDP-43 axonal accumulation in peripheral nerves originates from aberrant local synthesis.
• Muscle-derived miR-126a-5p EVs drive this non-cell-autonomous process, prompting presynaptic TDP-43 synthesis and accumulation.
• Inhibition of miR-126a-5p secretion exacerbates axonal translation disruption and NMJ degeneration.
• miR-126 administration demonstrated neuroprotective effects and delayed motor decline in ALS models.

Conclusions:

• A novel transcellular communication axis between muscles and motor neurons regulates axonal local synthesis and NMJ maintenance.
• Aberrant muscle-derived miR-126a-5p signaling contributes to TDP-43 pathology and NMJ degeneration in ALS.
• Targeting this muscle-neuron communication pathway holds potential for ALS therapeutic strategies.