NEUR3301 Growth and Trophic Factors 2024 PDF

Growth and Trophic Factors NEUR3301 Stuart Hodgetts  Growth and Trophic Factors Learning outcomes from this lecture: Role of growth and trophic factors in: Proliferation Soluble/diffusible factors - polypeptides Differentiation...

Growth and Trophic Factors NEUR3301 Stuart Hodgetts  Growth and Trophic Factors Learning outcomes from this lecture: Role of growth and trophic factors in: Proliferation Soluble/diffusible factors - polypeptides Differentiation Survival Innervation Maintenance Plasticity, learning and memory Regeneration and repair Retrograde and anterograde transport Targets Paracrine and autocrine functions Receptors and signal transduction Interactions with many other neuroactive molecules  Growth and Trophic Factors Soluble/diffusible factors - polypeptides Classically, target-derived neurotrophic factors should be: “produced and released in limited quantities in the projection areas of the responsive neurons, and regulate the extent of the survival and differentiation of these neurons during embryonic development and the maintenance of their specific function in adulthood” Hans Thoenen During development, competition for trophic support – amount and/or quality? The fittest survive?? Examples of growth or trophic factors: Neurotrophins (NTs), fibroblast growth factors (FGFs), cytokines (CNTF, LIF), transforming growth factors (TGFβ, GDNF etc), insulin-like growth factors (IGF-1) etc Harvey, Lovett, Majda, Yoon, Wheeler, Hodgetts “Neurotrophic factors for spinal cord repair: which, where, how and when to apply, and for what period of time?” (2015) Brain Research 1619: 36-71 Invited Review Hodgetts, S. & Harvey, A. R. (2016). “Neurotrophins in Spinal Cord Repair” in “NEUROTROPHINS”, Vitamins and Hormones, Academic Press/Elsevier – Invited Chapter Retrograde influences on neuronal viability and phenotype Short-range tropic effects as well? Synaptogenesis etc....  DRG explants - NGF NGF – in PNS and CNS Pro-NGF, cleaved to NGF + NGF dimer, two identical subunits, 118aa Neurite outgrowth and survival Whisker barrels - mouse Nerve growth factor – NGF Innervated by sensory neurons Iodinylated NGF Retrogradely transported from limb (target) back to cell body in DRG Additional NGF helps keep more cells alive Has to reach cell body to do this Fluorescence In situ hybridisation (FISH) Neurotrophin family: Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin 4/5 Actions of neurotrophins are mediated by specific receptors (Trk = receptor tyrosine kinases) that activate intracellular signalling pathways Trk receptor tyrosine kinases and major signal transduction pathways NOTE - receptor isoforms: full-length and truncated versions Reference only Thiele C J et al. Clin Cancer Res 2009;15:5962-5967 Receptor-receptor/protein interactions Teng et al., Dev Neurobiol. 2010 AKT Apoptosis Axonal Pruning Proneurotrophins p75 receptor MAPK Depending on which are co-expressed and co-activated – different outcome Crucial in our understanding of how to manipulate responses Nogo = myelin associated protein that inhibits axon outgrowth Lingo = Leucine rich repeat and Immunoglobin-like domain-containing protein 1 (co-receptor for Nogo)  NGF ▪ Maintenance role in mature nervous system? ▪ In CNS, relevance to synaptic plasticity? ▪ Alzheimer’s disease? Memory, cognition ▪ Expression after injury Sciatic nerve – mRNA (Schwann cells) PNS – complex interactions – see later To stimulate repair Neurotrophin-3 (NT3) Seen very early in development, mitogen for neural crest cells, differentiation Supports some DRG neurons (e.g. large proprioceptive) Differentiation effects in CNS, motoneurons, corticospinal neurons Brain-derived neurotrophic factor (BDNF) Periphery - Supports some DRG neurons, parasympathetic neurons Concentration in brain 20x higher than NGF Expressed in many regions – e.g. trophic for dopaminergic and GABAergic neurons, and supports many cells in visual system Arborization factor for some neurons including retinal ganglion cells Involved in activity-mediated synaptic plasticity Importance in the hippocampus – neurogenesis (exercise etc.) Sensory Para Symp Distinct neuronal subtypes depend on different neurotrophic factors Axonal transport along microtubules Some single population cells – make their own BDNF (antero) Target – makes its own BDNF (retro) How does cell know which is which? Sanes et al. (2006) Differential tagging  Exercise and trophic factor production in the adult brain Hippocampus Learning, memory Complex interactions involving neurotrophins – cooperative or antagonistic Schematic presentation of regulation of neurotrophin synthesis and release in neurons Neural activity is important Depolarization produced by release of glutamate (Glu) or acetylcholine (ACh) increases production of NGF and BDNF mRNAs Conversely, NGF and BDNF enhance ACh release from septal cholinergic nerve endings BDNF also increases release of glutamate from presynaptic terminals, induces NT-3 mRNA production and increases intracellular calcium levels in hippocampal neurons BDNF also phosphorylates some subunits of NMDA receptors post-synaptically Release of the inhibitory neurotransmitter GABA reduces neurotrophin mRNA levels  BDNF Synthesized as precursor “pre-proBDNF” protein, then cleaved to 32-kDa “pro-BDNF” protein Pro-BDNF either proteolytically cleaved intracellularly by enzymes & secreted as 14kDa mature BDNF (mBDNF), or secreted as pro-BDNF, then cleaved by extracellular proteases to mBDNF proBDNF and mBDNF preferentially sorted & packaged into vesicles of activity-regulated secretory pathway. ProBDNF not an inactive precursor of BDNF, but is a signalling protein in its own right ProBDNF is released in immature (especially) and mature CNS in an activity dependent manner Schematic representation of human BDNF gene structure and its splicing variants. Open boxes represent exons. Lines connect two exons. Arrows indicate alternative polyadenylation sites (PolyA) in 3′UTR and internal alternative splice sites in exons 2, 6, 7 and 9a (letters a, b, c and d). Ciliary neurotrophic factor – CNTF, (LIF) Glial differentiation CNTF Survival factor for sympathetic, sensory and spinal motoneurons CNTFRα Injury-induced effects Axon elongation factor LIFRβ gp 130 Retinal ganglion cells JAK/STAT BUT: Cytosolic not secretory protein ?! Mitogen activated Phosphotidylinosite-3 protein kinase kinase (MAPK) (PI-3K) Biological functions LIF = Leukemia Inhibitory Factor SOCS genes – negative regulators  Reference only Responsiveness to neurotrophic factor delivery – Spinal Cord Injury Axonal population Neurotrophic factor Corticospinal NT-3 (CNTF?) Rubrospinal BDNF, NT-4/5, GDNF Reticulospinal BDNF, NT-4/5, GDNF Raphe-spinal BDNF, NT-4/5, IGF-I, GDNF Ascending primary proprioceptive sensory NT-3, GDNF Propriospinal BDNF, NT-3, NT-4/5, GDNF Nociceptive sensory NGF, BDNF, GDNF Clarke’s nucleus - proprioceptive BDNF NT, neurotrophin; BDNF, brain-derived neurotrophic factor; GDNF, glial cell line-derived neurotrophic factor; IGF, insulin-like growth factor; NGF, nerve growth factor. Table 35.1 (Blesch et al., 2012) – Handbook of Clinical Neurology  Growth Factor Therapy in SCI NT-3 neurotrophin 3 BDNF brain-derived neurotrophic factor All Promote Axonal Growth After SCI GDNF glial cell line-derived neurotrophic factor NGF nerve growth factor bFGF basic fibroblast growth factor Enhance growth and function, Rescue axotomised CNS neurons and reduce atrophy Prolong normally transient expression of regeneration- associated genes after SCI Delivered virally and/or in scaffolds Delivered With cells (OEGs, SCs, NPCs) Harvey, Lovett, Majda, Yoon, Wheeler, Hodgetts “Neurotrophic factors for spinal cord repair: which, where, how and when to apply, and for what period of time?” (2015) Brain Research 1619: 36-71 Hodgetts, S. & Harvey, A. R. (2016). “Neurotrophins in Spinal Cord Repair” in “NEUROTROPHINS”, Vitamins and Hormones, Academic Press/Elsevier  Tissue Engineering - Bio-Scaffolds Type Cells used in Biohybrid Employed as Drug Grafts Material Natural Synthetic Delivery System Biodegradable Polarized Agarose √ BDNF, Others √ Alginate √ BDNF √ FB Chitosan √ NT-3, Others √ NPC, SC Collagen √ BDNF, NT-3 √ NA, SC, FB, OEG Fibrin √ NT-3 √ SC, OEG, ESNPC Fibronectin √ BDNF, NT-3 √ Matrigel √ GDNF, BDNF, NT-3 √ SC, ONP Methylcellulose √ bFGF √ Nitrocellulose √ NGF √ PEG √ NT-3, Others PLA, PGA, and PLGA √ Others √ SC, OEG, NA, FB pHEMA and HPMA √ Others Polypyrroles √ √ Reference only FB = fibroblasts; NA = neonatal astrocytes; SC = Schwann cells; OEG = olfactory ensheathing glia; NPC = adult brain derived neural progenitor cells; ONP = adult human olfactory neural progenitor cells; ESNPC = embryonic stem cell derived neural progenitor cells GDNF = glial cell line-derived neurotrophic factor, NT-3 = neurotrophin 3, BDNF = brain-derived neurotrophic factor, NGF = nerve growth factor, bFGF = basic fibroblast growth factor Sakiyama-Elbert, S.E., Johnson, P.J., Hodgetts, S. Plant, G.W. and Harvey, A.R. (2012) Handbook of Clinical Neurology -, Vol. 109 (3rd series) Volume on Spinal Cord Trauma. Chapter 36: “Artificial scaffolds to promote spinal cord regeneration” J. Verhaagen and J.W. McDonald III, Editors Chapter 36, p575  Additional Reading Helpful reviews and papers - and if you are keen to explore further….. Morel et al. 2020. Revisiting the Role of Neurotrophic Factors in Inflammation. Cells. 9(4): 865 Lin and Huang 2020. Brain-derived neurotrophic factor and mental disorders. Biomed J. 43(2):134-142 Palasz et al. 2020. BDNF as a Promising Therapeutic Agent in Parkinson's Disease. Int J Mol Sci. 21(3):1170 Foldvari M, Chen DW. Neural Regen Res. 2016 Jun;11(6):875-7. The intricacies of neurotrophic factor therapy for retinal ganglion cell rescue in glaucoma: a case for gene therapy. Pearn et al. Cell Mol Neurobiol. 2016 Jul 6. Review. Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics. Landowski LM, et al. J Chem Neuroanat. 2016 May 2. pii: S0891-0618(16)30070-9. Axonopathy in peripheral neuropathies: Mechanisms and therapeutic approaches for regeneration. Kelleher JH, et al. Neurobiol Dis. 2016 Apr 7. pii: S0969-9961(16)30071-7. Neurotrophic factors and their inhibitors in chronic pain treatment. Vilar M & Mira H. Front Neurosci. 2016 Feb 9;10:26. doi: 10.3389/fnins.2016.00026. Regulation of Neurogenesis by Neurotrophins during Adulthood: Expected and Unexpected Roles. Doron-Mandel E, et al. FEBS Lett. 2015 Jun 22;589(14):1669-77. Growth control mechanisms in neuronal regeneration. Hoyng SA, et al. Exp Neurol. 2014 Nov;261:578-93. Comparative morphological, electrophysiological & functional analysis of axon regeneration thro peripheral nerve autografts genetically modified to overexpress BDNF, CNTF, GDNF, NGF, NT3 or VEGF.  Additional Reading Helpful reviews and papers - and if you are keen to explore further….. English AW, et al Physiology (Bethesda). 2014 Nov;29(6):437-45. Exercise, neurotrophins, and axon regeneration in the PNS. Armada-da-Silva PA, et al. Int Rev Neurobiol. 2013;109:125-49. Role of physical exercise for improving posttraumatic nerve regeneration. Doron-Mandel E, et al. FEBS Lett. 2015 Jun 22;589(14):1669-77. Growth control mechanisms in neuronal regeneration. Razavi S, et al. Adv Biomed Res. 2015 Feb 17;4:53 Neurotrophic factors and their effects in the treatment of multiple sclerosis. Serafini G, et al. CNS Neurol Disord Drug Targets. 2014;13(10):1708-21 Hippocampal neurogenesis, neurotrophic factors and depression: possible therapeutic targets? Gonzalez A, et al. Cytoskeleton (Hoboken). 2016 May 25. doi: 10.1002/cm.21312 Cellular and molecular mechanisms regulating neuronal growth by brain-derived neurotrophic factor (BDNF). Pasquin S, et al. Cytokine Growth Factor Rev. 2015 Oct;26(5):507-15 Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies.