TY - JOUR
T1 - Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing
AU - Vahsen, Björn Friedhelm
AU - Ribas, Vinicius Toledo
AU - Sundermeyer, Jonas
AU - Boecker, Alexander
AU - Dambeck, Vivian
AU - Lenz, Christof
AU - Shomroni, Orr
AU - Caldi Gomes, Lucas
AU - Tatenhorst, Lars
AU - Barski, Elisabeth
AU - Roser, Anna Elisa
AU - Michel, Uwe
AU - Urlaub, Henning
AU - Salinas, Gabriela
AU - Bähr, Mathias
AU - Koch, Jan Christoph
AU - Lingor, Paul
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084159754&partnerID=8YFLogxK
U2 - 10.1038/s41418-020-0543-y
DO - 10.1038/s41418-020-0543-y
M3 - Article
C2 - 32341448
AN - SCOPUS:85084159754
SN - 1350-9047
VL - 27
SP - 2810
EP - 2827
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 10
ER -