Absence of the axon initial segment in sensory neuron enhances resistance to amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Proteasome dysfunction in ALS is considered to cause the accumulation of protein aggregates, which leads to motor neuron degeneration; however, the resilience of motor neurons to ALS pathology might be impaired long before the appearance of protein aggregates. Intriguingly, sensory dorsal root ganglion (DRG) neurons are not susceptible to ALS pathology despite their processes coexisting with axons of motor neurons in the same spinal nerves. Both DRG neurons and motor neurons in ALS model mice express activating transcription factor 3 (ATF3), a well-known marker of nerve injury and disease progression, suggesting that both types of neurons respond to ALS pathology. However, it remains unknown why only DRG neurons are resilient to ALS pathological damage. To address this issue, we used a nerve injury model in combination with unique injury-induced genetically engineered mice, in which genetic control with an Atf3 regulatory element enables proteasome ablation and mitochondrial visualization specifically in damaged neurons. Using the strategy, we found that DRG neurons are resistant to damage in proteasome-deficient conditions, whereas spinal motor neurons degenerate in the same conditions. This might be because DRG neurons lack the typical axon initial segment (AIS), which normally exists in mature neurons and acts as a gate for the selective transport of cargo to axons. The absence of a typical AIS in DRG neurons facilitated increased entry of mitochondria into the axon upon injury, with or without proteasome function. In contrast, damaged motor neurons lacking the proteasome failed to disassemble the AIS, which prevented increased mitochondrial influx into axons and led to energy depletion and degeneration. In the absence of the AIS, DRG neurons in the ALS mouse model are able to deliver sufficient mitochondria into the axon to prevent pathological damage. However, impaired proteasome function in ALS motor neurons results in retention of the AIS gate and failure of mitochondrial transport to axons. This is a possible reason why DRG neurons have greater resilience to ALS pathological damage compared with spinal motor neurons. Collectively, this study opens new directions for the understanding of neurodegenerative diseases at early stages of disturbed protein homeostasis.