Retinoic Acid (RA)
Recent research has spotlighted retinoic acid (RA) as an intriguing possibility for further exploration as a treatment for Huntington’s disease. Retinoic acid is derived from a compound that we know as Vitamin A, which is fat-soluble and primarily found in two forms: retinol and carotenoids. Retinoic acid is synthesized in the body from retinol, which is derived from a precursor found in animal foods such as milk and eggs. Once in the body, the precursor is converted to retinol, which then undergoes a series of reactions to form RA.
Retinoic acid is a biological molecule that regulates gene expression throughout the body and is crucial for cell differentiation and proliferation. These functions of RA have made it a useful treatment for skin diseases and cancer. In addition to the body, RA may regulate the expression of many proteins in the brain. Most proteins in the RA signaling pathway have been identified in the brain, including many that are adversely affected in HD. Nevertheless, little is currently known about where RA acts in the brain, what specific proteins it affects, or how its signaling relates to brain function, so much work still needs to be done to identify RA’s functions.
RA Signaling and Function^
Some evidence suggests that RA may play a role in gene transcription and cell differentiation. RA binds to specialized receptors in the cell nucleus, where transcription takes place, and can activate a large number of molecules within the cell. These molecules include enzymes, transcription factors, and inflammatory agents (i.e. cytokines and cytokine receptors), all of which are important in regulating crucial biological functions. RA may, for instance, send a signal that causes stem cells to become neurons. In fact the compound has been used in research for years, as a differentiation agent that can produce many types of early neural cells. When RA is absent, its receptors can also act as gene repressors, turning off gene transcription and thus inhibiting certain functions.
RA was first recognized as a key mediator of early development. It forms a concentration gradient across developing embryonic tissues and thereby governs the pattern of gene expression. This pattern regulation promotes development of different parts of the body depending on what genes are switched on. This property of RA was demonstrated by an experiment conducted on tadpole embryos. In this experiment, researchers noticed that concentrations of RA were much higher in the posterior (back or tail) end of the tadpole embryo than in the anterior (front or head) end. They exposed the embryo to elevated RA, and as a result, certain structures in the anterior end (such as the brain) failed to develop properly. This finding implied that different parts of the embryo required different amounts of RA, and receiving more or less than the required amount interfered with vital developmental processes (Altaba & Jessell, 1991).
It was later discovered that RA acts in a similar fashion in the adult brain, in which gene transcription is also controlled through varying RA concentrations. Several important functions found to be regulated by the RA pathway include spatial learning, long-term potentiation (LTP), synaptic plasticity, and nerve regeneration.
Implications for HD^
RA may play a role in motor disorders such as Parkinson’s disease (PD) and HD since it is involved in the function of the striatum, a brain structure involved in planning and execution of movement and that undergoes cell death in HD. RA promotes neuron formation and differentiation in the striatum, which receives RA from the substantia nigra, a midbrain structure that is also important for motor planning. Neurons in the substantia nigra express high levels of an enzyme that catalyzes RA synthesis. This enzyme travels along the neurons extending from the substantia nigra to the striatum, where it can help generate RA. In studies of HD transgenic mice, it was found that more than 20% of the genes in the striatum that showed diminished expression contained elements of the RA signaling pathway. This result could suggest that some type of defect in the RA pathway contributes to HD. Further research is needed to determine whether a defective RA pathway could relate to HD motor symptoms.
Several discoveries suggest that RA may be able to treat key pathological symptoms of HD, making it a candidate therapeutic for the disease. For instance, huntingtin aggregates, which form in the brains of HD patients, interfere with RA signaling. These aggregates disrupt the activity of a protein called PGC1-alpha, which in turn disturbs the protein PPAR-delta, which mediates cellular responses to RA. PPAR-delta function is significantly diminished in HD mouse models, implicating PPAR-delta in the pathology of the disease. (You can read more about this study here). Drugs that target the RA signaling pathway are currently on the market to treat tumors and cancers such as leukemia. Further investigation of RA and the RA signaling pathway could open the door to a potential treatment for HD, maybe by enhancing the retinoic acid pathway through PPAR-delta. Proof of such a hypothesis remains a topic of developing preliminary research.
For Further Reading^
Altaba, A. Ruiz i, and T. Jessell. “Retinoic acid modifies mesodermal patterning in early Xenopus embryos.” Genes & Development 5 (1991): 175-187. This study has a lot of technical language, but most of the key points have been summarized above in the RA Signaling and Function section.
Duester, Gregg. “Retinoic Acid Synthesis and Signaling during Early Organogenesis.” Cell 134.6 (2008): 921-931. Web. 13 Apr 2011. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632951/pdf/nihms76219.pdf>. This is a very in-depth article about the synthesis and function of RA. Some technical language.
Luthi-Carter, R, A Strand, NL Peters, SM Solano, and others. “Decreased expression of striatal signaling genes in a mouse model of Huntington.” Hum Mol Genet 9.9 (2000): 1259-71. Web. 13 Apr 2011. <http://hmg.oxfordjournals.org/content/9/9/1259.full>. The main point to take away from this study is that “mutant huntingtin directly or indirectly reduces the expression of a distinct set of genes involved in signaling pathways known to be critical to striatal neuron function.”
Mey, Jörg, & McCaffery, Peter. Retinoic acid signaling in the nervous system of adult vertebrates. The Neuroscientist 10.5 (2004). Web. 13 Apr 2011. <http://www.accutaneaction.com/Studies/2004_Mey.pdf>. This contains some technical language, but it has a lot of interesting information about RA research and treatment possibilities.
J. Nguyen 2011