User talk:Anders Lewisesquerre: Difference between revisions
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== Brain-derived neurotrophic factor (BDNF) == | == Brain-derived neurotrophic factor (BDNF) == | ||
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== Introduction == | == Introduction == | ||
Brain-derived neurotrophic factor (BDNF) is a 13kDa signaling protein belonging to the neurotrophin family of growth factors. This family of growth factors are critical in the development, differentiation, and survival of neurons. Mammalian members of the neurotrophin family of growth factors include Nerve growth factor (NGF) [https://www.rcsb.org/structure/6XUO PDB structure], neurotrophin-3 (NT-3) [https://www.rcsb.org/structure/1B8K PDB structure], and neurotrophin-4/5 (NT-4/5)[https://www.rcsb.org/structure/1B98 PDB structure of neurotrophin-4/5]. BDNF is primarily expressed in the brain, where it is found in the hippocampus, cortex, amygdala, and striatum, and less so in the hypothalamus. BDNF is also expressed in peripheral tissues, such as the kidneys, retina, prostate, motor neurons, skeletal muscle. | Brain-derived neurotrophic factor (BDNF) is a 13kDa signaling protein belonging to the neurotrophin family of growth factors. This family of growth factors are critical in the development, differentiation, and survival of neurons. Mammalian members of the neurotrophin family of growth factors include Nerve growth factor (NGF) [https://www.rcsb.org/structure/6XUO PDB structure], neurotrophin-3 (NT-3) [https://www.rcsb.org/structure/1B8K PDB structure], and neurotrophin-4/5 (NT-4/5)[https://www.rcsb.org/structure/1B98 PDB structure of neurotrophin-4/5]. BDNF is primarily expressed in the brain, where it is found in the hippocampus, cortex, amygdala, and striatum, and less so in the hypothalamus. BDNF is also expressed in peripheral tissues, such as the kidneys, retina, prostate, motor neurons, skeletal muscle. | ||
== Function == | == Function == | ||
Brain-derived neurotrophic factor (BDNF) is involved in the growth, differentiation, and survival of neurons in the central, and peripheral nervous systems. It plays a role in neural plasticity, neurogenesis, energy metabolism, inflammation and immunity, neurotransmitter regulation, and potential roles in the cardiovascular system. The role of BDNF in neural plasticity is shown in its ability to regulate NDMA receptor signaling by increasing calcium influx and more BDNF release, which by retrograde signaling, enhances pre-synaptic vesicle cycling, thereby regulating long-term potentiation (LTP), and plasticity. | Brain-derived neurotrophic factor (BDNF) is involved in the growth, differentiation, and survival of neurons in the central, and peripheral nervous systems. It plays a role in neural plasticity, neurogenesis, energy metabolism, inflammation and immunity, neurotransmitter regulation, and potential roles in the cardiovascular system. The role of BDNF in neural plasticity is shown in its ability to regulate NDMA receptor signaling by increasing calcium influx and more BDNF release, which by retrograde signaling, enhances pre-synaptic vesicle cycling, thereby regulating long-term potentiation (LTP), and plasticity. | ||
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The third cascade is the '''PLC/DAG/IP3 pathway''', where | The third cascade is the '''PLC/DAG/IP3 pathway''', where | ||
PLC-𝛾 is phosphorylated by BDNF binding to the TrkB receptor, leading to production of IP3 and DAG. IP3 increases intracellular calcium concentrations, and DAG regulates protein kinase C, which is important in the MAPK/ERK pathway. | PLC-𝛾 is phosphorylated by BDNF binding to the TrkB receptor, leading to production of IP3 and DAG. IP3 increases intracellular calcium concentrations, and DAG regulates protein kinase C, which is important in the MAPK/ERK pathway. | ||
== Structure == | == Structure == | ||
<scene name='10/1078788/Bdnf/1'>BDNF</scene><Structure load='1b8m' size='350' frame='true' align='right' caption='BDNF' scene='10/1078788/Bdnf/1' /> is a 13kDa protein that belongs to the nerve growth factor (NGF) family. In a broader sense, BDNF is part of the cystine-knot cytokine superfamily. A cystine-knot is a structural motif characterized by three intertwined disulfide bonds that form a knot. This <scene name='10/1078788/Bdnf_disulfide_bonds_2/1'>Cystine knot</scene>, which has three disulfide bonds and is likely a key structural feature that allows binding to the TrkB receptor. The protein is composed mostly of 𝛽-sheets, with the exception of the small, single alpha helical turn from amino acid residues 22-26. There are also notable flexible regions in the protein that consist of 𝛽-turns, and intrinsically disordered regions (IDRs). A ConSurf-DB analysis was done on BDNF to identify conserved sequences on the protein. The analysis results identified residues running along the long middle portions of 𝛽-sheets. This may provide insight into regions of BDNF receptor binding, where the less conserved regions may vary from species to species due to the differing physiology of such species. | <scene name='10/1078788/Bdnf/1'>BDNF</scene><Structure load='1b8m' size='350' frame='true' align='right' caption='BDNF' scene='10/1078788/Bdnf/1' /> is a 13kDa protein that belongs to the nerve growth factor (NGF) family. In a broader sense, BDNF is part of the cystine-knot cytokine superfamily. A cystine-knot is a structural motif characterized by three intertwined disulfide bonds that form a knot. This <scene name='10/1078788/Bdnf_disulfide_bonds_2/1'>Cystine knot</scene>, which has three disulfide bonds and is likely a key structural feature that allows binding to the TrkB receptor. The protein is composed mostly of 𝛽-sheets, with the exception of the small, <scene name='10/1078788/Bdnf_residues_22-26/1'>single alpha helical turn</scene> from amino acid residues 22-26. There are also notable flexible regions in the protein that consist of 𝛽-turns, and intrinsically disordered regions (IDRs). A ConSurf-DB analysis was done on BDNF to identify conserved sequences on the protein. The analysis results identified residues running along the long middle portions of 𝛽-sheets. This may provide insight into regions of BDNF receptor binding, where the less conserved regions may vary from species to species due to the differing physiology of such species. | ||
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== Disease == | == Disease == | ||
Implicated in multiple neurodegenerative diseases due to its apparent neuroprotective effects, ability to promote neurogenesis, and improve synaptic plasticity. Lower BDNF levels are seen in patients with Multiple Sclerosis (MS), Parkinson's disease, and Alzheimer's disease, which highlights the consequence that lower amounts of BDNF contribute to the cognitive decline seen in Alzheimer’s, and dopaminergic neuron degeneration seen in parkinsons. Hungtinton’s disease, which is caused by a mutation in the huntingtin gene, produces a mutated huntingtin protein that disrupts BDNF axonal transport and transcription. Because striatal neurons heavily rely on cortically derived BDNF for survival and function, this disruption leads to the degeneration of striatal neurons, a key pathological feature of Hungtington’s disease. BDNF is also associated with type-2 diabetes mellitus by its regulation of energy metabolism, specifically increasing the amount of insulin secreting granules in pancreatic 𝛃 cells through TrkB signal pathways. | Implicated in multiple neurodegenerative diseases due to its apparent neuroprotective effects, ability to promote neurogenesis, and improve synaptic plasticity. Lower BDNF levels are seen in patients with Multiple Sclerosis (MS), Parkinson's disease, and Alzheimer's disease, which highlights the consequence that lower amounts of BDNF contribute to the cognitive decline seen in Alzheimer’s, and dopaminergic neuron degeneration seen in parkinsons. Hungtinton’s disease, which is caused by a mutation in the huntingtin gene, produces a mutated huntingtin protein that disrupts BDNF axonal transport and transcription. Because striatal neurons heavily rely on cortically derived BDNF for survival and function, this disruption leads to the degeneration of striatal neurons, a key pathological feature of Hungtington’s disease. BDNF is also associated with type-2 diabetes mellitus by its regulation of energy metabolism, specifically increasing the amount of insulin secreting granules in pancreatic 𝛃 cells through TrkB signal pathways. | ||
== Val66Met polymorphism == | == Val66Met polymorphism == | ||
A single nucleotide polymorphism has gained attention that involves a polymorphism at codon 66 in the BDNF gene that results in a point mutation swapping a valine for a methionine. While the mutation change does not make it into the final processed mature BDNF protein, it is known to induce impacts on the processing, transport, and potentially folding of the protein. Individuals with the met allele, especially homozygotes, have measurable effects on brain function caused by a decrease in the availability of BDNF at synapses as a result of the mutation. Individuals with this mutation may have decreased hippocampal volume and show symptoms of memory impairment. | A single nucleotide polymorphism has gained attention that involves a polymorphism at codon 66 in the BDNF gene that results in a point mutation swapping a valine for a methionine. While the mutation change does not make it into the final processed mature BDNF protein, it is known to induce impacts on the processing, transport, and potentially folding of the protein. Individuals with the met allele, especially homozygotes, have measurable effects on brain function caused by a decrease in the availability of BDNF at synapses as a result of the mutation. Individuals with this mutation may have decreased hippocampal volume and show symptoms of memory impairment. | ||
== Additional resources == | == Additional resources == | ||
[https://consurf.tau.ac.il/consurf_index.php ConSurf] | [https://consurf.tau.ac.il/consurf_index.php ConSurf] | ||
