Targeting Motor Neuron - Immune System Crosstalk to Modulate the Disease Progression in Amyotrophic Lateral Sclerosis Mouse Model

Trolese, Maria Chiara (2021). Targeting Motor Neuron - Immune System Crosstalk to Modulate the Disease Progression in Amyotrophic Lateral Sclerosis Mouse Model. PhD thesis The Open University.



ALS is a fatal neurodegenerative disease characterised by remarked heterogeneity, which might stem from the multisystemic, non-cell-autonomous and complex nature of the disease.

The early deterioration of the peripheral compartment has led to ALS being recognised as distal axonopathy, whereby muscles and nerves actively contribute to neurodegeneration. However, the contribution of the inflammatory response in the CNS starkly contrasts to the periphery, revealing its pivotal role at promoting phenomena of protection and/or toxicity.

We corroborated these observations showing a higher activation of the MCP1 chemokine within MNs and peripheral compartment of C57SOD1G93A than 129SvSOD1G93A mice. Therefore, we surmised that the higher peripheral degeneration and faster disease progression of 129SvSOD1G93A mice stemmed from this defective immune response.

To decipher the contribution of the peripheral immune response in ALS progression, the therapeutic potential of MCP1 was assessed. The chemokine was induced alongside the motor units of the two SOD1G93A models through a single intramuscular injection of a scAAV9 vector engineered with MCP1 (scAAV9_MCP1).

The scAAV9_MCP1-mediated boosting of the immune response prevented the degeneration of the peripheral compartment whilst the chemokine induction within MNs led to a neuroprotective activity, resulting in the amelioration of the clinical phenotype in C57SOD1G93A but not 129SvSOD1G93A mice.

This discrepancy pointed the nature and temporal activation of the immune response out as discriminating factors to promote the peripheral compartment regeneration and slow-down ALS progression.

The analysis of ALS patients muscles validated our findings, demonstrating a direct correlation between the immune cells inflammatory fingerprint and the rate of the disease progression. These observations candidate the peripheral compartment as a primary target for the development of therapeutic interventions effective at influencing the ALS progression. Moreover, the comprehension of the MCP1 role within the motor unit of SOD1G93A mice might provide innovative evidence regarding the contribution of the immune response in ALS.

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