A mutation in the protein huntingtin causes the devastating neurodegenerative disorder Huntington's disease (HD).
Huntingtin is a high-molecular-weight, ubiquitously expressed protein that has no sequence homology with other proteins and a fundamental role in embryonic development. It seems to have appeared some millions of years ago, before the divergence of the protostoma (which gave rise to insects) and deuterostoma (mammals) branches.
Biological evidence shows that huntingtin is anti-apoptotic in vitro and in vivo. This cell-autonomous activity can be shown in neuronal and non-neuronal cells, and is contained in the 548 amino acid terminus (N548) of the protein. In addition, huntingtin protects neurons from excitotoxicity in vivo.
In the search for additional functions of wild-type huntingtin that could be more neuron-specific, huntingtin was found to stimulate brain-derived neurotrophic factor (BDNF) gene transcription through inhibition of a silencer element (Repressor element 1, also known as neuron-restrictive silencer element, NRSE) located in the promoter of the BDNF gene. Through a similar mechanism, huntingtin controls the transcription of many other neuronal genes that carry an RE1/NRSE in their promoters. Wild-type huntingtin also regulates fast axonal trafficking, vesicle transport (including transport of BDNF) and synaptic transmission, and so has a crucial role in normal brain function.
Mutation of huntingtin causes reduced BDNF production, enhanced activity of the RE1/NRSE silencer (with repression of neuronal gene transcription), reduced transport of mitochondria and BDNF, altered synaptic transmission and many other alterations as a consequence of its increased toxicity.
Whereas increased expression of wild-type huntingtin leads to increased survival and BDNF production, its depletion produces some (but not all) of the phenotypes observed in HD mice. This suggests that reduced huntingtin activity might have a role in HD and that wild-type huntingtin might act as a modifier of HD pathology.
Wild-type huntingtin levels have been manipulated by its overexpression or depletion in HD models. Its overexpression reduces mutant huntingtin toxicity in HD cells in vitro and in the testes of HD transgenic mice. Its reduced level in HD mice causes a worsening of some of the HD phenotypes. Finally, reducing the level of BDNF in HD mice causes earlier onset of symptoms and increased motor dysfunction.
Huntingtin is, therefore, endowed with important functions in the healthy brain. Some of these same functions are reduced in HD, so wild-type huntingtin might act as a modifier of HD pathology. Restoring the activity of its downstream targets could be beneficial to patients with this disorder.
Several neurological diseases are characterized by the altered activity of one or a few ubiquitously expressed cell proteins, but it is not known how these normal proteins turn into harmful executors of selective neuronal cell death. We selected huntingtin in Huntington's disease to explore this question because the dominant inheritance pattern of the disease seems to exclude the possibility that the wild-type protein has a role in the natural history of this condition. However, even in this extreme case, there is considerable evidence that normal huntingtin is important for neuronal function and that the activity of some of its downstream effectors, such as brain-derived neurotrophic factor, is reduced in Huntington's disease.
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The work described in this review has been supported by grants from the Huntington's Disease Society of America (HDSA; USA), the Hereditary Disease Foundation (HDF; USA), HighQ Foundation (USA), Telethon (Italy), the Cariplo Foundation (Italy), Ministero dell'Istruzione dell'Universita' e della Ricerca (Italy) and the European Commission Framework VI Programme (NeuroNE). E.C. is member and coordinator of the 'Huntingtin Function' HDSA Coalition For the Cure Team. We apologize for the omission of a number of significant papers that could not be cited because of space limitations.
The authors declare no competing financial interests.
- RNA INTERFERENCE
(RNAi). A method by which double-stranded RNA that is encoded on an exogenous vector can be used to interfere with normal RNA processing, causing rapid degradation of the endogenous RNA and thereby precluding translation. This provides a simple way of studying the effects of the absence of a gene product in simple organisms and in cells.
- POLAR ZIPPER
A term used by Max Perutz to describe a three-dimensional protein motif consisting of interactions between polar residues on separate subunits or separate proteins.
- EXTRA-EMBRYONIC TISSUE
All tissues that do not contribute to the embryo but support its development.
- VISCERAL ENDODERM
Extra-embryonic tissue in pre-gastrulation stages of the mouse embryo.
The events involved in the development of an organism, from the earliest embryonic stage to maturity.
The events involved in the evolution of a species.
The birth of new neurons, which occurs not only in developing organisms but also throughout adult life in both vertebrates and invertebrates. Ongoing neurogenesis is thought to be an important mechanism underlying neuronal plasticity, allowing organisms to adapt to environmental changes, and influencing learning and memory throughout life.
An organism that is composed of cells derived from at least two genetically different zygotes.
Describes a mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.
- CRE/LOXP SITE-SPECIFIC RECOMBINATION SYSTEM
A system derived from the Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre-recombinase enzyme catalyses recombination between the loxP sites, which leads to excision of the intervening sequence. This tool is used at late stages of maturation or in the adult to study the function of genes whose deletion causes embryonic lethality.
Cellular toxicity involving the activation of glutamate receptors in the CNS. Glutamate, an excitatory amino acid neurotransmitter, activates different types of ionotropic (ion channel-forming) and metabotropic (G-protein-coupled) receptor. Excessive activation of these receptors by high concentrations of glutamate or by neurotoxins acting at the same receptors leads to cell death.
- CORTICO-STRIATAL SYNAPSE
Cortical afferents reaching the striatum are intermingled with other cellular elements (the striatal targets, dopaminergic inputs and glial cells), which may be able to influence the output of the cortex. The activity of each of these cellular elements is finely regulated through a complex interplay between the receptor systems they express.
- FAST AXONAL TRAFFICKING
Several motor proteins move various cargoes on microtubule tracks — such as membrane organelles, protein complexes, complexes of nucleic acids, signalling molecules, neuroprotective and repair molecules, and vesicular and cytoskeletal components — to deliver them from the neuronal cell body through the long axon to their final destination.
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Cattaneo, E., Zuccato, C. & Tartari, M. Normal huntingtin function: an alternative approach to Huntington's disease. Nat Rev Neurosci 6, 919–930 (2005). https://doi.org/10.1038/nrn1806
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