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Neurotrophic Factors and Huntington’s Disease

Neurotrophic factors are proteins that promote the development, maintenance and survival of neurons in the brain. These factors have been shown to increase the function of nerve cells as well as protect diseased neurons from dying. There are often higher levels of neurotrophic factors in areas with local neuronal damage, meaning that neurotrophic factors might be involved in neuronal rescue and regeneration. A chronic absence of these essential proteins eventually leads to apoptosis, the death of specific populations of neurons in the brain.

cells hypothesis kinases

NGF Superfamily (neurotrophins)^

In 1987, a neutrophic factor called nerve growth factor (NGF) was discovered. The study of NGF led to the Neurotrophic Factor Hypothesis, which suggested that neurons must compete with each other for specific survival factors. A useful analogy would be to imagine growing two plants in a pot. These two plants must compete for the limited amounts of nutrients in the soil, and the plant better able to take up nutrients would be more likely to survive. The Neurotrophic Factor Hypothesis proposes that the availability or absence of neurotrophic factors determines whether a given neuron will live or die. Today, researchers believe that almost all cells are likely to depend on their interactions with neighboring cells for survival. Since the discovery of NGF, three other molecules of this family have been characterized—brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4). The first three neurotrophins (NGF, BDNF and NT-3) are expressed in the basal ganglia, which means that they may be involved in neurodegenerative disorders that affect that region of the brain, such as Huntington’s disease (HD).

TGFß Superfamily^

The transforming growth factor-ß (TGFß) superfamily consists of three subfamilies of neurotrophic factors. Of particular interest are the glial cell line-derived neurotrophic factor (GNDF) family, which consists of four proteins, GNDF, neurturin, persephin and artemin. These factors are known to affect different parts of the central nervous system. For example, GNDF and neuturin have been found in the striatum and have been shown to promote the survival of motor neurons, which are commonly affected in HD.

Neurokine Superfamily^

The neurokine superfamily includes proteins such as ciliary neurotrophic factor (CNTF), which has functions in the central nervous system. Synthesized by astrocytes, CNTF is believed to be a key player in the nervous system’s response to injury and has been shown to protect damaged neurons in vitro.

Non-neuronal Growth Factors^

Although non-neuronal growth factors affect many different physiological processes, they have been found at high concentrations in the nervous system. For example, almost all regions of the brain exhibit receptors for insulin-like growth factor-1 (IGF-1), a protein that has been shown to be a survival factor for neuronal cells in laboratory cultures.

The Importance of Receptors^

In order for neurotrophic factors to affect neurons, they must first bind to their respective receptors. The structure, function and location of these receptors vary greatly between different neurotrophic factors. For example, in the NGF superfamily, there are two main types of receptors— 1) tyrosine receptor kinases that bind specific neurotrophins with high affinity, meaning very tightly and, 2) the p75 neurotrophin receptor that binds all four types of neurotrophins with relatively low affinity, or less tightly. The low affinity p75 receptor appears to enhance the signaling of the high-affinity tyrosine receptor kinases. Scientists are studying not only how these receptors respond to their neurotrophic factors, but also how they interact with each other. Understanding the function of these receptors is crucial for developing therapeutic uses for neurotrophic factors, as these protective molecules are only valuable if they are recognized by the targeted neurons.

Neurotrophic Factors and Huntington’s Disease^

Researchers are interested in the protective qualities of neurotrophic factors because of their role in neurodegenerative disorders, such as Huntington’s disease (HD). One of the most striking physiological characteristics of HD is the loss of neurons in the striatum, a component of the basal ganglia system that organizes motor movement. In particular, there is a loss of the spiny neurons that compose 95% of the striatum. In recent years, there has been considerable research not only on the affect of HD on neurotrophic factor levels, but also the protective roles that neurotrophic factors can play in preventing neurodegeneration. For example, mutated huntingtin has been shown to down-regulate the expression of BDNF. In turn, the decreased expression of BDNF in HD has been implicated in the progressive loss of neurons in the striatum (For more information on this topic, see the section on BDNF). Transplanted cells in the striatum that are engineered to over-express GNDF and neurturin have also been shown to protect neighboring neurons from excitotoxic attacks (for more information, see our section on the excitatoxic model of Huntington’s disease. In cellular models of HD, treatment with CNTF has been shown to protect spiny neurons from the apoptotic pathway induced by mutant huntingtin. (To read more about the apoptotic pathway, click here.) These examples highlight not only the complex interactions between HD and neurotrophic factors, but also the therapeutic potential of these protective proteins.

However, there are still obstacles to developing effective neurotrophic factor-based therapies for neurodegenerative diseases. Although the protective effects of neurotrophic factors are well-known, the therapeutic potential of these proteins will depend on the ability to effectively deliver these factors into the desired regions of the brain. Neurotrophic factors do not easily cross the blood-brain barrier and thus, must be administered in large doses in order to have an effect on the target region(s). To avoid technical challenges and side effects of large doses, scientists are looking for ways to directly introduce neurotrophic factors into regions with damaged neurons. One method is directly injecting neurotrophic factors into the brain. Another strategy involves injecting genetically engineered cells that over-express certain neurotrophic factors into the central nervous system. However, these methods are limited by their invasiveness and the extent to which these neurotrophic factorstravel in the brain. Recent research has looked into using viral vectors to provide continuous, long-term delivery of neurotrophic factors. This technique would incorporate the DNA code to make neurotrophic factors into the genome of a virus. These viruses then enter our body’s neurons and use the nerve cells’ own machinery to make the specific neurotrophic factors encoded by the DNA. Despite the challenges, there is a great deal of interest in one day using neurotrophic factors as a therapy for HD.

Further Reading^

  • Alexi, T. et al. (2000) Neuroprotective strategies for basal degeneration: Parkinson’s and Huntington’s diseases. Progress in Neurobiology 60: 409-470.This paper provides an exhaustive overview of the many different factors that are being examined for therapeutic potential in Parkinson’s and Huntington’s disease.
  • Dawbarn, D. & Allen, S.J. (2003) Neurotrophins and neurodegeneration. Neuropathology and Applied Neurobiology 29: 211-230.This paper focuses on the role of neurotrophins in three neurodegenerative diseases: Alzheimer’s, Parkinson’s and Huntington’s diseases. There is a large focus on recent experiments.
  • Chao, M.V., Rajagopal, R. & Lee, F.S. (2006) Neurotrophin signaling in health and disease. Clinical Science 110: 167-173.This article goes into detailed descriptions of how neurotrophic factor signaling works, but also has a relatively accessible section on the therapeutic potential of neurotrophins.
  • Alberch, J., Pérez-Navarro, E. & Canals, J.M. Neurotrophic factors in Huntington’s disease. Progress in Brain Research 146: 195-229.This article provides a detailed review of the research being done on the role of neurotrophic factors in HD. The language is very technical, with very frequent references to the findings of recent experiments.
  • Levy, Y.S., Gilgun-Sherki, Y., Melamed, E. & Offen, D. (2005) Therapeutic potential of neurotrophic factors in neurodegenerative diseases. Biodrugs 19: 97-127.This paper provides an overview of all the neurotrophic superfamilies. While some of the language is very technical, it does a good job of summarizing many different neurotrophic factors.
  • Weis, J., Saxena, S., Evangelopoulos, M.E. & Kruttgen, A. (55) Trophic factors in neurodegenerative diseases. Life 55: 353-357.This article goes into considerable detail about the mechanisms of neurotrophic factor signaling, especially in neurodegenerative diseases.
  • Huang, E.J. & Reichardt, L.F. (2001) Neurotrophins: Roles in neuronal development and function. Annual Review of Neuroscience 24: 677-736.This article provides an extremely comprehensive overview of neurotrophins.

-Y. Lu , 6/18/2009