The human motor neuron axonal transcriptome is enriched for transcripts related to mitochondrial function and microtubule-based axonal transport

Abstract Local axonal translation of specific mRNA species plays an important role in axon maintenance, plasticity during development and recovery from injury. Recently, disrupted axonal mRNA transport and translation have been linked to neurodegenerative disorders. To identify mRNA species that are actively transported to axons and play an important role in axonal physiology, we mapped the axonal transcriptome of human induced pluripotent stem cell (iPSC)-derived motor neurons using permeable inserts to obtain large amounts of enriched axonal material for RNA isolation and sequencing. Motor neurons from healthy subjects were used to determine differences in gene expression profiles between neuronal somatodendritic and axonal compartments. Our results demonstrate that several transcripts were enriched in either the axon or neuronal bodies. Gene ontology analysis demonstrated enrichment in the axonal compartment for transcripts associated with mitochondrial electron transport, microtubule-based axonal transport and ER-associated protein catabolism. These results suggest that local translation of mRNAs is required to meet the high-energy demand of axons and to support microtubule-based axonal transport. Interestingly, several transcripts related to human genetic disorders associated with axonal degeneration (inherited axonopathies) were identified among the mRNA species enriched in motor axons.