Abstract:
:Axonal degeneration is an initial key step in traumatic and neurodegenerative CNS disorders. We established a unique in vivo epifluorescence imaging paradigm to characterize very early events in axonal degeneration in the rat optic nerve. Single retinal ganglion cell axons were visualized by AAV-mediated expression of dsRed and this allowed the quantification of postlesional acute axonal degeneration (AAD). EM analysis revealed severe structural alterations of the cytoskeleton, cytoplasmatic vacuolization, and the appearance of autophagosomes within the first hours after lesion. Inhibition of autophagy resulted in an attenuation of acute axonal degeneration. Furthermore, a rapid increase of intraaxonal calcium levels following crush lesion could be visualized using a calcium-sensitive dye. Application of calcium channel inhibitors prevented crush-induced calcium increase and markedly attenuated axonal degeneration, whereas application of a calcium ionophore aggravated the degenerative phenotype. We finally demonstrate that increased postlesional autophagy is calcium dependent and thus mechanistically link autophagy and intraaxonal calcium levels. Both processes are proposed to be major targets for the manipulation of axonal degeneration in future therapeutic settings.
journal_name
Proc Natl Acad Sci U S Aauthors
Knöferle J,Koch JC,Ostendorf T,Michel U,Planchamp V,Vutova P,Tönges L,Stadelmann C,Brück W,Bähr M,Lingor Pdoi
10.1073/pnas.0909794107subject
Has Abstractpub_date
2010-03-30 00:00:00pages
6064-9issue
13eissn
0027-8424issn
1091-6490pii
0909794107journal_volume
107pub_type
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