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The Hippocampal Autophagic Machinery is Depressed in the Absence of the Circadian Clock Protein PER1 that may Lead to Vulnerability During Cerebral Ischemia

[ Vol. 14 , Issue. 3 ]

Author(s):

Abdelhaq Rami*, Julia Fekadu and Oliver Rawashdeh   Pages 207 - 214 ( 8 )

Abstract:


Background: Autophagy is an intracellular bulk self-degrading process in which cytoplasmic contents of abnormal proteins and excess or damaged organelles are sequestered into autophagosomes, and degraded upon fusion with lysosomes. Although autophagy is generally considered to be pro-survival, it also functions in cell death processes. We recently reported on the hippocampal, higher vulnerability to cerebral ischemia in mice lacking the circadian clock protein PERIOD1 (PER1), a phenomenon we found to be linked to a PER1-dependent modulation of the expression patterns of apoptotic/autophagic markers.

Methods: To exclude the contribution of vascular or glial factors to the innate vulnerability of Per1 knockout-mice (Per1−/−-mice) to cerebral ischemia in vivo, we compared the autophagic machinery between primary hippocampal cultures from wild-type (WT)- and Per1−/−-mice, using the lipophilic macrolide antibiotic, Rapamycin to induce autophagy.

Results: Development of autophagy in WT cells involved an increased LC3-II-to-LC3-I ratio (microtubule-associated protein 1 light chain 3) and an overall increase in the level of LC3-II. In addition, immunostaining of LC3 in WT cells revealed the typical transformation of LC3 localization from a diffused staining to a dot- and ring-like pattern. In contrast, Per1−/−-hippocampal cells were resistant to Rapamycin induced alterations of autophagy hallmarks.

Conclusion: Our in vitro data suggests that basal activity of autophagy seems to be modulated by PER1, and confirms the in vivo data by showing that the autophagic machinery is depressed in Per1−/−-hippocampal neurons.The implication of both autophagy and circadian dysfunction in the pathogenesis of cerebral ischemia suggests that a functional connection between the two processes may exist.

Keywords:

Per-1 clock gene, autophagy, hippocampal neurons, neuronal vulnerability, rapamycin, cerebral ischemia.

Affiliation:

Institut für Anatomie III, Theodor- Stern-Kai 7, 60590 Frankfurt/Main, Institute of Cellular and Molecular Anatomy (Anatomy III), Dr. Senckenbergische Anatomie, Clinics of the Johann Wolfgang von Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Institute of Cellular and Molecular Anatomy (Anatomy III), Dr. Senckenbergische Anatomie, Clinics of the Johann Wolfgang von Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main



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