Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth

Abstract

The establishment of neuronal polarity and axonal outgrowth are key processes affecting neuronal migration and synapse formation, their impairment likely leading to cognitive deficits. Here we have found that the apoptotic protease activating factor 1 (Apaf1), apart from its canonical role in apoptosis, plays an additional function in cortical neurons, where its deficiency specifically impairs axonal growth. Given the central role played by centrosomes and microtubules in the polarized extension of the axon, our data suggest that Apaf1-deletion affects axonal outgrowth through an impairment of centrosome organization. In line with this, centrosomal protein expression, as well as their centrosomal localization proved to be altered upon Apaf1-deletion. Strikingly, we also found that Apaf1-loss affects trans-Golgi components and leads to a robust activation of AMP-dependent protein kinase (AMPK), this confirming the stressful conditions induced by Apaf1-deficiency. Since AMPK hyper-phosphorylation is known to impair a proper axon elongation, our finding contributes to explain the effect of Apaf1-deficiency on axogenesis. We also discovered that the signaling pathways mediating axonal growth and involving glycogen synthase kinase-3β, liver kinase B1, and collapsing-response mediator protein-2 are altered in Apaf1-KO neurons. Overall, our results reveal a novel non-apoptotic role for Apaf1 in axonal outgrowth, suggesting that the neuronal phenotype due to Apaf1-deletion could not only be fully ascribed to apoptosis inhibition, but might also be the result of defects in axogenesis. The discovery of new molecules involved in axonal elongation has a clinical relevance since it might help to explain neurological abnormalities occurring during early brain development.

Chemotherapeutic Drugs and Mitochondrial Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib

“…In line with this, cardiomyopathy of mice with cardiac-specific deletion of HER2 might be rescued by the antiapoptotic Bcl-xL which supports the reversibility of cardiac toxicity associated with HER2 inhibition [ 105 ] by trastuzumab. Indeed, while blocking the ErbB2 signaling by trastuzumab leads to apoptosis of cancer cells [ 116 ], cardiomyocytes are particularly resistant to mitochondrial apoptosis [ 105 , 106 ] possibly due to the increased expression of X-linked inhibitor of apoptosis (XIAP) and decreased expression of apoptotic protease activating factor-1 (Apaf1) [ 117 , 118 ].…”

Acute Noise Exposure Is Associated With Intrinsic Apoptosis in Murine Central Auditory Pathway

“…On the other hand, APAF1 protein is supposed to function as a pro-survival molecule, which absence impairs the cell performance and increases responsiveness to stressful conditions. Thus, a compensatory reduction of Apaf1 mRNA expression could probably be accompanied by a negative impact on the structural and functional arrangement of mitochondrial homeostasis and might further contribute to the long-term physiological deficits and pathologies after noise exposure (Ferraro et al, 2011 ; Sancho et al, 2014 ; De Zio et al, 2015 ).…”

The mitochondrial metabolic reprogramming agent trimetazidine as an ‘exercise mimetic’ in cachectic C26‐bearing mice

“…Data were normalized to 18S, and a calibrator was used as internal control. Resulting data were analysed by the MX3PRO (v4.10), and fold change was determined by using the 2‐ΔΔCT method . All reactions were performed in triplicate.…”