PDF《BDNF function in health and disease》

Neurotransmitter release Caspase

3 Golgi apparatus Endoplasmic reticulum Promoter IV Dense-core vesicle CaRF CREB Ca2+ Truncated TRKB BDNF Dendrite NMDAR activation and membrane depolarization Local translation Presynaptic Postsynaptic Sortilin SORCS2 p75NTR Prodomain Extracellular processing by MMPs or plasmin Intracellular processing by furin or proconvertases Di?erential sorting to the constitutive or regulated secretory pathways ↓ RAC ↑ RHO PLCγ1 Ca2+ MEK1/2 ERK1/2 SHC GRB2 FRS2 SOS GAB1 DAG PKC CREB IP3 PI3K RAS RAF mTOR CAMK AKT Protein translation Gene expression Neuronal survival, di?erentiation and synaptic plasticity Astrocyte Ca2+ CaMKII cAMP Alternatively spliced mRNAs Nucleus Coding sequence BDNF Poly(A) I II III IV V VI VII VIII IX 5′ 3′

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Post-transcription The nine exons of the BDNF gene (white boxes) can be alternatively spliced to produce transcripts with di?erent 5′ and 3′ untranslated regions that share the same common coding region (part of exon IX). BDNF mRNA can be di?erentially sorted to neuronal compartments, including dendrites, where it can undergo local translation. 6. Extracellular processing ProBDNF can be cleaved extracellularly by plasmin or by selective matrix metalloproteinases (MMPs) (MMP3, MMP7 and MMP9) to release BDNF and the isolated prodomain. 1. Transcription BDNF has nine exons (white boxes numbered ICIX) and, in rodents and humans, has nine promoters (not shown). Promoter IV can be induced by neural activity, NMDA receptor (NMDAR) activation, calcium in?ux and cAMP-responsive element-binding protein (CREB) activation. BDNF promoters are also regulated epigenetically by histone acetylation and methylation, and repressed by methyl-CpG-binding protein

2 (MECP2), which can be released from the promoter by CaMKII activity. 4. Intracellular processing ProBDNF can be cleaved by furin or proconvertases in the trans-Golgi network or secretory vesicles, respectively, to release BDNF and the prodomain. ProBDNF, BDNF and the isolated prodomain can be secreted from neurons. Sortilin P P Growth cone retraction proBDNF Presynaptic Postsynaptic ↑ Surface expression and conductance Nav PLCγ Ca2+ RHO CaMKII cAMP PKA Synapsin MAPK Gene expression RAB3A Long-term synaptic plasticity Retrograde transport of signalling endosome to soma NMDAR P Kv Phosphorylation and changes in conductance PI3K AKT Local mRNA translation Apoptosis Gene expression GABAR AMPAR ↓ Surface expression PKC TRPC Long-term synaptic plasticity Actin polymerization ↑ Ca2+ MAPK Dendritic growth and spine maturation Retrograde transport of signalling endosome to soma Internalization of TRKBCBDNF complex Local actions of BDNF at a synapse

5 TRKB

7 7. BDNF in astrocytes Astrocytes can respond to locally generated BDNF by the activation of truncated TRKB receptors in their cell surface. This can regulate astrocytic morphology and also astrocytic activation in disease states.

5 JNK Apoptosis CDK5 RAC TIAM1 PAK Actin dynamics CYFIP1 FMRP MECP2 3. Tra?cking ProBDNF consists of a prodomain (green) and mature BDNF (red) and is synthesized in the endoplasmic reticulum. After passing through the Golgi apparatus, it is packaged into dense-core vesicles and can be tra?cked through regulated or constitutive secretory pathways. 5. Receptors????? BDNF isoforms elicit distinct cellular functions depending on the di?erential expression of their receptors. Pre- or postsynaptic tyrosine kinase TRKB (also known as NTRK2) receptors bind BDNF to promote neuronal survival, di?erentiation and synaptic plasticity. Moreover, a splice variant of TRKB lacking the tyrosine kinase domain (truncated TRKB) sequesters BDNF and can signal independently. ProBDNF binds to a complex of p75 neurotrophin receptor (p75NTR) and sortilin or SORCS2 (members of the VPS10P domain-sorting receptor family) to induce long-term depression, growth cone retraction or apoptosis. The isolated Met66 prodomain can bind to SORCS2 to induce growth cone retraction in a p75NTR-dependent manner (see Val66Met substitution box). ? TRKBCBDNF complex Unfolded proBDNF Pathological roles and therapeutic challenges Alterations in BDNF levels are associated with neurodegenerative disorders (including Alzheimer'