Abstract
Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes Kif1b and Ddit3. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target.
Highlights
In both traumatic and neurodegenerative disorders of the CNS, axonal degeneration occurs early in the disease course and frequently precedes neuronal cell death [1,2,3,4]
We overexpress Unc-51 like autophagy activating kinase 1 (ULK1).DN, which is comprised of only the C-terminal amino acids 829–1051 and lacks the kinase domain [15]
ULK1.DN moderately inhibits autophagy activation after administration of rapamycin. This is in line with experiments using ULK1.siRNA and ULK1 knockout, where a moderate inhibitory effect on autophagy and no complete blockage was seen [13, 15, 53]
Summary
In both traumatic and neurodegenerative disorders of the CNS, axonal degeneration occurs early in the disease course and frequently precedes neuronal cell death [1,2,3,4]. Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances. During AAD, one of the first steps is rapid intra-axonal calcium influx leading to the activation of calpain proteases and macroautophagy (here, autophagy) [7, 8]. Inhibition of calcium channels and calpain successfully attenuate AAD [8,9,10]. The role of autophagy in axonal degeneration, remains not fully understood
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