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Summary
This summary is machine-generated.

Lorlatinib, an ALK inhibitor, shows promise for treating frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by rescuing synaptic deficits caused by C9orf72 gene mutations. This therapy normalizes neuronal function and enhances resilience to excitotoxicity.

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Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Hexanucleotide repeat expansions in C9orf72 are the leading genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
  • C9orf72 haploinsufficiency disrupts synaptic function, leading to altered neuronal morphology and protein expression, which are key in FTD pathogenesis.
  • Lorlatinib, an ALK inhibitor, influences actin dynamics via the PI3K-LIMK-cofilin pathway, suggesting potential therapeutic applications.

Purpose of the Study:

  • To investigate the therapeutic potential of lorlatinib in mitigating synaptic dysfunction associated with C9orf72 haploinsufficiency.
  • To evaluate lorlatinib's effects on neuronal morphology and resilience to excitotoxicity in a cellular model of C9orf72-related FTD.

Main Methods:

  • Primary cortical neurons from C9orf72+/- mouse embryos were utilized.
  • Dendritic arborization and vulnerability to glutamate excitotoxicity were assessed.
  • Immunocytochemistry and immunoblots were employed to analyze dendritic complexity and protein expression at DIV12-15.

Main Results:

  • Neurons with C9orf72 haploinsufficiency displayed altered dendritic branching and increased vulnerability to glutamate excitotoxicity and cell death.
  • Elevated GluA1 levels at post-synaptic sites contributed to excitotoxicity, driven by aberrant PI3K/Akt and LIMK1/cofilin pathway activity.
  • Lorlatinib treatment rescued dendritic complexity and enhanced neuronal resilience by normalizing PI3K/Akt and LIMK1/cofilin pathway activity.

Conclusions:

  • Lorlatinib demonstrates significant therapeutic potential for synaptic deficits in C9orf72 haploinsufficiency.
  • Targeting ALK with lorlatinib offers a promising strategy for treating synaptic dysfunction in C9orf72-related FTD.
  • The study underscores the critical role of synaptic pathology in C9orf72-FTD pathogenesis.