BDNF pro-peptide regulates dendritic spines via caspase-3.
The precursor of brain-derived neurotrophic factor (BDNF) (proBDNF) is enzymatically cleaved, by either intracellular (furin/PC1) or extracellular proteases (tPA/plasmin/MMP), to generate mature BDNF (mBDNF) and its pro-peptide (BDNF pro-peptide). Little is known about the function of BDNF pro-peptide. We have developed an antibody that specifically detects cleaved BDNF pro-peptide, but not proBDNF or mBDNF. Neuronal depolarization elicited a marked increase in extracellular BDNF pro-peptide, suggesting activity-dependent regulation of its extracellular levels. Exposure of BDNF pro-peptide to mature hippocampal neurons in culture dramatically reduced dendritic spine density. This effect was mediated by caspase-3, as revealed by studies with pharmacological inhibitors and genetic knockdown. BDNF pro-peptide also increased the number of 'elongated' mitochondria and cytosolic cytochrome c, suggesting the involvement of mitochondrial-caspase-3 pathway. These results, along with BDNF pro-peptide effects recently reported on growth cones and long-term depression (LTD), suggest that BDNF pro-peptide is a negative regulator of neuronal structure and function.
Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China.|Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
J
J
Guo
Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China.
Y
Y
Ji
Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China.
Y
Y
Ding
Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China.
W
W
Jiang
Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
Y
Y
Sun
School of Medicine, Tsinghua University, Beijing 100084, China.
B
B
Lu
Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China.
G
G
Nagappan
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D061251:Primary Cell Culture; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction
D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D011994:Recombinant Proteins; C426674:brain-derived neurotrophic factor precursor; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3