Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked to neuroinflammation driven by RNA-binding proteins like TDP-43 and FUS in astrocytes.
• Reactive astrocytes contribute to neuronal injury in these neurodegenerative diseases.
• Dehydrocostus lactone (DHE), a blood-brain barrier-permeable compound, possesses anti-inflammatory properties and is a potential therapeutic candidate.

Purpose of the Study:

• To investigate the therapeutic potential of DHE in ALS and FTD.
• To elucidate the molecular mechanisms underlying DHE's neuroprotective effects.
• To evaluate DHE's efficacy in preclinical models of ALS/FTD.

Main Methods:

• DHE's effects were tested in primary mouse and human astrocytes, patient-derived fibroblasts, and cortical neurons.
• Drosophila models with FUS or TDP-43 mutations were used to assess DHE's in vivo efficacy.
• Molecular analyses included NF-κB and NRF2 signaling, protein aggregation, mitochondrial function, and inflammatory mediator assessment.

Main Results:

• DHE suppressed NF-κB-driven inflammation and activated NRF2-mediated antioxidant pathways in astrocytes with TDP-43 or FUS pathology.
• DHE reduced astrocyte-mediated neurotoxicity, improved neuronal mitochondrial function, and decreased pathological FUS aggregation.
• DHE treatment improved locomotor function and survival in Drosophila models and reduced elevated chemokine levels in ALS patient plasma.

Conclusions:

• DHE mitigates astrocyte-driven neurotoxicity in ALS/FTD by suppressing inflammation and enhancing antioxidant defenses.
• Therapeutic effects were consistent across cellular, patient-derived, and in vivo models.
• DHE represents a promising therapeutic strategy for ALS/FTD, targeting astrocyte-mediated signaling pathways.