Human induced pluripotent stem cell (hiPSC)-derived sensory neuronal cultures highly enriched in primary proprioceptive neurons (PPNs) showed altered transcriptomic and proteomic profiles, defective neurite extension, and abnormal electrophysiological properties, according to a new study published in Brain Communications. The abnormal development and selective loss of proprioceptive neurons are hallmarks of Friedreich ataxia (FA).
“Our results suggest that in FA, PPNs might not be able to properly reach and innervate their targets in muscles or in the spinal cord. Since proper targeting is critical for neuronal survival, this could consequently lead to proprioceptive degeneration,” the study’s authors explained.
Transcriptomic and proteomic analyses suggested alterations in the organization of axonal cytoskeleton at the growth cone, neurite extension and axon guidance, and, at later stages of maturation, in synaptic plasticity and chemical transmission of FA neurons.
Although both FA and control neurons were able to extend long neurites, the longest axons of FA neurons were defective, with tortuous or twisted appearance. Moreover, FA neurons showed a reduction in firing frequencies compared to control neurons.
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Dionisi et al have also identified epigenetic differences between FA and control cells, including altered acetylation and increased trimethylation in histone H3 lysine 9 and lysine 27 in FA. Increased trimethylation was mainly observed in the regions upstream and downstream of the GAA repeats.
“Our study provides new and more specific insights into the pathological features of PPNs in FA and highlights the need for a further investigation of the role of GAA expansion mutation and frataxin deficiency in PPNs degeneration in FA,” the study’s authors said.
The hiPSCs used in the study were obtained from a reprogramming of human fibroblasts or peripheral blood mononuclear cells from 5 patients with FA and 2 healthy donors. In addition, Dionisi et al used 3 FA sibling isogenic controls.
Dionisi C, Chazalon M, Rai M, et al. Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties. Brain Commun. 2023;5(1):fcad007. doi:10.1093/braincomms/fcad007