Full-length reviewThe role of neuronal growth factors in neurodegenerative disorders of the human brain
Introduction
Neuronal cell death as a result of neurotrophic factor deprivation is a physiological cell death mechanism which is commonly observed during neuronal development 14, 201, 236, 359. Many neurons within the vertebrate nervous system require the presence of neurotrophic factors such as nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) for survival 14, 359. It has been proposed that growing axons compete for limited amounts of neurotrophic factors which are produced by the target tissues. Neurons which fail to obtain a sufficient quantity of the necessary neurotrophic factor die by a process of programmed cell death [14]. This process is thought to regulate the number of neurons and neuronal connections within the developing central nervous system (CNS). The neurotrophic factor family has been proposed to play a role in the neuroprotection of specific neuronal populations by suppressing the expression of `suicide genes' which, when activated are involved in the induction of apoptotic processes 14, 236, 359. This proposal suggests that when the level of neurotrophic factor expression fall below that required to suppress the activation of `suicide genes', transcriptional processes may result in the induction of apoptotic mechanisms.
While the mechanisms involved in the neuronal loss that occurs following a reduction in neurotrophic support have been determined in the developing nervous system, researchers are still unclear as to what implications deficits in trophic support have in the adult CNS. While it has been observed that several neuronal populations within the adult CNS require the presence of neurotrophic factors to maintain neuronal function and phenotype 82, 88, 424, it is unclear as to the degree to which mature neurons remain dependent upon target-derived support. If mature neurons are still dependent upon the presence of neurotrophic factors for survival and function then the loss of transcriptional suppression of the `suicide programme' due to a reduction in neurotrophic factor expression may result in the neuronal atrophy seen in normal aging or the neuronal loss observed in neurodegenerative disorders such as Alzheimer's disease (AD) [236]. Indeed, it has been proposed 20, 189that AD pathology may primarily be due to a deficit in neurotrophic factor protein and/or tyrosine kinase (trk) receptor expression.
Research is currently being undertaken in order to determine whether members of the neurotrophic factor family have potential therapeutic roles in preventing and/or reducing the neuronal cell loss and atrophy that occurs in neurodegenerative disorders such as AD, Parkinson's disease (PD), Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS). The use of neurotrophic factors as therapeutic agents is a novel approach aimed at restoring and maintaining neuronal function in the CNS. Neurotrophic factors have the potential to protect diseased and injured neurons from dying, induce neuronal sprouting and to increase neuronal metabolism and function. Research is currently being undertaken to determine potential mechanisms to deliver neurotrophic factors to selectively vulnerable regions of the CNS. However, while the expression of neurotrophic factors and their high-affinity trk receptors has been fully characterised in the rodent CNS, little research has been performed examining the expression and functional role of these factors in the normal and diseased human brain. In this review, we will discuss the regional distribution and functional role of individual neurotrophic factors and trk receptors in the CNS. We will also examine the role neurotrophic factors and trk receptors may play in the pathogenesis of neurodegenerative disorders, both in vitro and in vivo, with particular emphasis on the therapeutic use of these factors to prevent and/or reduce selective neuronal loss in the diseased human brain. The reader is referred to previous reviews discussing the pathophysiological aspects of human neurodegenerative disorders 50, 61, 64, 65, 126, 148, 176, 180, 183, 185, 214, 230, 231, 275, 373, 406. Throughout this review, the term neurotrophin/neurotrophic factor will be loosely used to cover members of the NGF family (NGF, BDNF and NT-3) and additional growth factors including insulin-like growth factor (IGF-I), glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-α (TGF-α).
Section snippets
Mechanisms of selective neuronal cell death in neurodegenerative disorders
Two mechanisms of neuronal cell death have been identified within the CNS—necrosis and apoptosis. Apoptosis is defined as a process of active cell death, characterised by cell and nuclear shrinkage, chromatin condensation and membrane blebbing. In contrast, necrosis has been characterised by cellular swelling and lysis resulting in a cytokine-mediated inflammatory response. While necrosis results in the appearance of random DNA fragmentation, apoptosis is associated with the cleavage of DNA
The function of NGF
NGF was first discovered by Levi-Montalcini in 1951 [287]. High concentrations of NGF were observed in the mouse submaxillary glands resulting in the cloning of the NGF gene in several species 150, 305, 401, 466. Since its discovery, NGF has become one of the best characterised members of the neurotrophin family. NGF consists of three subunits, α, β and γ which interact to form a 7S complex of approximately 27 kDa in weight. The 7S complex contains two identical 118 amino acid β chains which
Identification and cloning
A second target-derived neurotrophic factor, BDNF, has been detected within the CNS 305, 337. BDNF is a basic dimeric 28-kDa protein of non-covalently linked 14-kDa subunits structurally related to NGF 382, 383, 475. Recombinant human BDNF (rhBDNF) was recently cloned and the protein sequence of mature human BDNF was observed to be identical to the porcine and rat sequences indicating conservation across species [366].
Regional distribution of BDNF within the CNS
BDNF mRNA and protein levels have been detected in the hippocampus, amygdala,
Identification and cloning of NT-3
Utilising information obtained on the structural homology of the neurotrophic factor family, researchers cloned a gene encoding NT-3 135, 209, 304. The predicted size of the NT-3 polypeptide is 199 amino acids and the mature rat NT-3 peptide displays a 57% amino acid identity with rat NGF and a 58% amino acid identity with rat BDNF. However, despite this structural homology, NT-3 has distinct biological activity and a different spatiotemporal characteristic from both NGF and BDNF.
Regional distribution of NT-3 within the CNS
In contrast to
Identification of the structure and regional distribution
The observation that the rat glial cell line, B49 released a factor which exhibited relative specificity for dopaminergic neurons in dissociated cultures of the rat embryonic midbrain lead to the identification of a new member of the neurotrophic family 134, 291, 293. This potential neurotrophic factor was purified, cloned and identified as GDNF 291, 292. GDNF is a glycosylated, disulfide-bonded homodimer that is distantly related to members of the TGF-β superfamily. The molecular weight of the
The structure of TGF-α and the EGF/TGF-α receptor
TGF-α, a member of the epidermal growth factor (EGF) family of mitogenic polypeptides 66, 103, has also been observed to provide trophic support and promote the differentiation of CNS neurons in vitro. TGF-α was initially identified in the medium of retrovirus-transformed rodent cells 170, 306and extensive sequence homology was found among TGF polypeptides from different species and cell types. The mature 50 amino acid form of TGF-α is derived from a 160 amino acid transmembrane precursor by
Identification and regional distribution
Current research is also focused on determining the potential role members of the IGF family may have in preventing neuronal injury or reducing neuronal degeneration. The presence of IGFs and their receptors in the CNS has raised the possibility that the IGFs may play a role in brain development, neuronal and glial phenotypic differentiation, glial cell growth and neuronal outgrowth 37, 289. The IGFs are mitogenic polypeptides with insulin-like metabolic activity [352]and two IGF molecules,
The identification of binding sites for NGF—the dual receptor binding system
The receptor signaling system of the neurotrophic factor family is unique in that it consists of two transmembrane receptor proteins, the trk family of receptors and the low-affinity p75 receptor. Each of the neurotrophic factors are capable of interacting with the low-affinity p75 receptor and a specific trk receptor 35, 235, 305, 317. The first major study into the identification and description of NGF receptors focused on binding sites observed in chick sensory ganglia cells 100, 437. Two
Conclusion
In conclusion, the research to date indicates a potential role for neurotrophic factors in the treatment of neurodegenerative disorders. However, it still remains unclear as to whether alterations in neurotrophic factor or trk receptor expression are primary or secondary to the neuropathological changes associated with each disorder. Indeed, while it has not been determined whether alterations in neurotrophic factor or trk receptor expression precede the development of the disease process, it
Acknowledgements
This research was supported by the New Zealand Neurological Foundation, the Health Research Council of New Zealand, the New Zealand Lotteries Health Board and the Auckland University Research Committee. Bronwen Connor holds a Health Research Council of New Zealand Postgraduate Scholarship.
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