Frataxin depletion leads to decreased soma size and activation of AMPK metabolic pathway in dorsal root ganglia sensory neurons

Griso, O.; Chellapandi, D. M.; Weiss, A.; Manolaras, I.; Puccio, H.

doi:10.1101/2025.10.07.680891

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bioRxiv · 10.1101/2025.10.07.680891

Frataxin depletion leads to decreased soma size and activation of AMPK metabolic pathway in dorsal root ganglia sensory neurons

Griso, O.·Chellapandi, D. M.·Weiss, A.·Manolaras, I.·Puccio, H.

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Abstract

IntroductionFriedreichs ataxia (FA) is an inherited neurodegenerative disorder caused by frataxin deficiency, leading to impaired iron-sulfur (Fe-S) cluster biogenesis and mitochondrial dysfunction. Proprioceptive dorsal root ganglia (DRG) neurons are among the most vulnerable cell types in FA, yet the mechanisms underlying their selective susceptibility remain unclear. MethodsWe developed a primary culture model of embryonic mouse DRG neurons with complete frataxin depletion, enabling longitudinal analysis of cellular and metabolic alterations. ResultsThis novel model reproduces several key biochemical hallmarks of FA, including Fe-S enzyme deficiency, mitochondrial dysfunction, altered iron homeostasis and oxidative stress. Despite severe mitochondrial impairment, frataxin-deficient neurons remained viable but exhibited a marked reduction in soma growth. Mechanistically, this phenotype was associated with activation of AMP-activated protein kinase (AMPK) hyperactivation and inhibition of mTOR signaling. Genetics inhibition of AMPK or re-expression of frataxin restored neuronal growth, demonstrating a functional link between metabolic stress signaling and soma size regulation. Treatment with -lipoic acid (ALA) rescued soma growth, normalize ATP levels and reduce AMPK activation. ConclusionsOur findings identify AMPK-mTOR signaling as a key pathway linking mitochondrial dysfunction to impaired neuronal growth impairment in frataxin-deficient sensory neurons. This robust, scalable cellular model provides new insights into sensory neuron vulnerability and offers a platform for therapeutic discovery.

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Griso, O., Chellapandi, D. M., Weiss, A., Manolaras, I., Puccio, H.. 2025-10-07. Frataxin depletion leads to decreased soma size and activation of AMPK metabolic pathway in dorsal root ganglia sensory neurons. https://doi.org/10.1101/2025.10.07.680891

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