Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

Cells

Priya Nandy¹  SandraL. Siedlak¹  Xiongwei Zhu¹  Quillan Austria¹  Sandy Torres¹  Wenzhang Wang¹  Song Han¹  Hisashi Fujioka² 

[1] Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, OH 44106, USA;

关键词: mitofusin-2;    alzheimer’s disease;    neurodegeneration;    mitochondrial fragmentation;    oxidative stress;    mitochondrial ultrastructural damage;    aberrant cell-cycle event;    apoptosis;   

DOI  :  10.3390/cells9010116

来源: DOAJ

【 摘 要 】

It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer’s disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegeneration in the hippocampus and cortex. Here, we utilize an inducible mouse model to knock out Mfn2 (Mfn2 iKO) in adult mouse hippocampal and cortical neurons to avoid complications due to developmental changes. Electron microscopy shows the mitochondria become swollen with disorganized and degenerated cristae, accompanied by increased oxidative damage 8 weeks after induction, yet the neurons appear normal at the light level. At later timepoints, increased astrocyte and microglia activation appear and nuclei become shrunken and pyknotic. Apoptosis (Terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) begins to occur at 9 weeks, and by 12 weeks, most hippocampal neurons are degenerated, confirmed by loss of NeuN. Prior to the loss of NeuN, aberrant cell-cycle events as marked by proliferating cell nuclear antigen (PCNA) and pHistone3 were evident in some Mfn2 iKO neurons but do not colocalize with TUNEL signals. Thus, this study demonstrated that Mfn2 ablation and mitochondrial fragmentation in adult neurons cause neurodegeneration through oxidative stress and neuroinflammation in vivo via both apoptosis and aberrant cell-cycle-event-dependent cell death pathways.

【 授权许可】

Unknown