Wednesday 16 July 2003
Huntingtin acts on the transcription of brain-derived neurotrophic factor (BDNF) and of many other neuronal genes and on BDNF transport.
Wild-type huntingtin sequesters Repressor element 1 (RE1)-silencing transcription factor (REST, also known as neuronal restrictive silencing factor, NRSF) in the cytoplasm in such a way that the co-repressor complex does not form at the RE1 (also known as the neuron-restrictive silencer element, NRSE) sites and the BDNF gene is transcribed.
The asterisk indicates that wild-type huntingtin facilitates the transcription of many other RE1/NRSE-controlled neuronal genes (for example, synapsin I, pro-enkephalin, muscarinic acetylcholine receptor 4 and dynamin 1) as well as BDNF.
In Huntington’s disease, mutant huntingtin is less capable of retaining REST/NRSF in the cytoplasm, and it enters the nucleus where it leads to the formation of the repressor complex and reduced transcription of neuronal genes, including BDNF.
Wild-type huntingtin is also part of a motor complex that controls vesicle BDNF transport along microtubules: it binds to huntingtin-associated protein 1 (HAP1) and indirectly regulates the assembly of p150(Glued) with the dynein and dynactin complexes that ultimately control the microtubule transport of BDNF vesicles.
The transient binding of wild-type huntingtin with cytoskeletal proteins might allow the movement of the BDNF vesicles.
Under pathological conditions, mutant huntingtin binds more tightly to HAP1, reducing the transport of BDNF vesicles along microtubules.
The molecular chaperones Hsp70 and Hsp40 promote the folding of newly synthesized huntingtin (htt) into a native structure.
Wild-type htt is predominantly cytoplasmic and probably functions in vesicle transport, cytoskeletal anchoring, clathrin-mediated endocytosis, neuronal transport or postsynaptic signalling.
htt may be transported into the nucleus and have a role in transcriptional regulation.
mutations in Huntington disease
The HD mutation induces conformational changes and is likely to cause the abnormal folding of htt, which, if not corrected by chaperones, leads to the accumulation of misfolded htt in the cytoplasm.
Alternatively, mutant htt might also be proteolytically cleaved, giving rise to amino-terminal fragments that form -sheet structures.
Ultimately, toxicity might be elicited by mutant full-length htt or by cleaved N-terminal fragments, which may form soluble monomers, oligomers or large insoluble aggregates.
In the cytoplasm, mutant forms of htt may impair the ubiquitin–proteasome system (UPS), leading to the accumulation of more proteins that are misfolded.
These toxic proteins might also impair normal vesicle transport and clathrin-mediated endocytosis. Also, the presence of mutant htt could activate proapoptotic proteins directly or indirectly by mitochondrial damage, leading to greater cellular toxicity and other deleterious effects.
In an effort to protect itself, the cell accumulates toxic fragments into ubiquitinated cytoplasmic perinuclear aggregates.
In addition, mutant htt can be translocated into the nucleus to form nuclear inclusions, which may disrupt transcription and the UPS.
Amyloid and huntingtin
Huntington disease results from the aggregation of the neuronal protein huntingtin. Compared with the other conformational dementias, the appearance of intracellular inclusions is a late feature of the disease. The reason for this is that the initial aggregates are efficiently removed by cellular chaperones and it is only when these become overwhelmed, after many years, that the aggregates develop and with them the clinical manifestations.
The cause of the aggregation is the presence in the tail of the huntingtin molecule of a large glutamine-repeat domain that can undergo an inheritable extension. If the size of this domain extends beyond 37 repeats, then intermolecular bonding between tails forms the aggregates.
An intriguing explanation for the beta-linked structure of the huntingtin aggregates, which has wider implications for amyloids in general, has recently been proposed.
This model suggests that the glutamine repeats form a cylindrical sheet made up of beta-strands with 20 residues per helical turn, and provides a satisfying hypothesis for the crucial threshold of 37-40 glutamine repeats that are required for neurodegeneration in Huntington disease.
A single turn with 20 residues would be unstable, as there is nothing to hold it in place; however, 2 turns with 40 residues are stabilized by the hydrogen bonds between their amides, and such initial 2-turn structures can then act as nuclei for further helical growth.
Normal huntingtin function: an alternative approach to Huntington’s disease. Elena Cattaneo, Chiara Zuccato & Marzia Tartari. Nature Reviews Neuroscience 6, 919-930 (December 2005)