title: NP1 regulates neuronal activity-dependent accumulation of BAX in mitochondria and mitochondrial dynamics.
abstract: In cultured cerebellar granule neurons, low neuronal activity triggers the intrinsic program of apoptosis, which requires protein synthesis-dependent BAX translocation to mitochondria, a process that may underlie neuronal damage in neurodegeneration. However, the mechanisms that link neuronal activity with the induction of the mitochondrial program of apoptosis remain unclear. Neuronal pentraxin 1 (NP1) is a pro-apoptotic protein induced by low neuronal activity that is increased in damaged neurites in Alzheimer's disease-affected brains. Here we report that NP1 facilitates the accumulation of BAX in mitochondria and regulates mitochondrial dynamics during apoptosis in rat and mouse cerebellar granule neurons in culture. Reduction of neuronal activity increases NP1 protein levels in mitochondria and contributes to mitochondrial fragmentation in a Bax-dependent manner. In addition, NP1 is involved in mitochondrial transport in healthy neurons. These results show that NP1 is targeted to mitochondria acting upstream of BAX and uncover a novel function for NP1 in the regulation of mitochondrial dynamics and trafficking during apoptotic neurodegeneration.
authors.affiliation: Neurobiology Unit, Biomedical Research Institute of Barcelona, Consejo Superior de Investigaciones Científicas, Institute of Biomedical Research August Pi i Sunyer, 08036 Barcelona, Spain.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Clayton
authors.forename: Petar
authors.initials: P
authors.lastname: Podlesniy
authors.forename: Joana
authors.initials: J
authors.lastname: Figueiro-Silva
authors.forename: Guillermo
authors.initials: G
authors.lastname: López-Doménech
authors.forename: Lluis
authors.initials: L
authors.lastname: Benitez
authors.forename: Marta
authors.initials: M
authors.lastname: Enguita
authors.forename: Maria A
authors.initials: MA
authors.lastname: Abad
authors.forename: Eduardo
authors.initials: E
authors.lastname: Soriano
authors.forename: Ramon
authors.initials: R
authors.lastname: Trullas
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002097:C-Reactive Protein / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D009419:Nerve Tissue Proteins; D051028:bcl-2-Associated X Protein; D000099153:Pentraxins; C494827:Bax protein, mouse