title: Autophagy, and BiP level decrease are early key events in retrograde degeneration of motoneurons.
abstract: Disconnection of the axon from the soma of spinal motoneurons (MNs) leads either to a retrograde degenerative process or to a regenerative reaction, depending on the severity and the proximity to the soma of the axonal lesion. The endoplasmic reticulum (ER) is a continuous membranous network that extends from the nucleus to the entire cytoplasm of the neuronal soma, axon and dendrites. We investigated whether axonal injury is sensed by the ER and triggers the activation of protective mechanisms, such as the unfolded protein response (UPR) and autophagy. We found early (at 3 days) accumulation of beclin1, LC3II and Lamp-1, hallmarks of autophagy, in both degenerating MNs after spinal root avulsion and in non-degenerating MNs after distal nerve section, although Lamp-1 disappeared by 5 days only in the former. In contrast, only degenerating MNs presented early activation of IRE1α, revealed by an increase of the spliced isoform of Xbp1 and accumulation of ATF4 in their nucleus, two branches of the UPR, and late BiP downregulation in association with cytoskeletal and organelle disorganization. We conclude that BiP decrease is a signature of the degenerating process, as its overexpression led to an increase in MN survival after root avulsion. Besides, Bcl2 is strongly implicated in the survival pathway activated by BiP overexpression.
authors: Group of Neuroplasticity and Regeneration, Institute of Neurosciences, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors: C
authors: C
authors: Penas
authors: M
authors: M
authors: Font-Nieves
authors: J
authors: J
authors: Forés
authors: V
authors: V
authors: Petegnief
authors: A
authors: A
authors: Planas
authors: X
authors: X
authors: Navarro
authors: C
authors: C
authors: Casas
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071701:Regulatory Factor X Transcription Factors; D012183:Retrograde Degeneration / Q000378:metabolism*; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D000091342:Endoplasmic Reticulum Chaperone BiP; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D051701:Activating Transcription Factor 4; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D051907:Lysosomal Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C497110:Atf4 protein, rat; C512829:Becn1 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C489117:Lamp1 protein, rat; D052118:Lysosomal-Associated Membrane Protein 1; C000605545:Xbp1 protein, rat