By: Lise Munsie, PhD
In cell biology…
The exact molecular mechanism of the huntingtin (Htt) protein is largely unknown. A paper from Dr. Solomon Snyder’s lab at Johns Hopkins that probes the link between Htt and the striatal-specific protein Rhes was recently published in the Journal of Biological Chemistry.1 This paper implicates Rhes in mTOR-independent autophagy, and demonstrates that binding of mutant Htt (mHtt) with Rhes inhibits the autophagic function of Rhes in a PC12 cell model. Autophagy becomes more important in aging cells; therefore, alterations to Rhes in HD could explain striatal-specific degeneration, as well as the late-onset characteristics of HD.
Transcriptional dysregulation is another known factor in the progression of HD. A recent report in Human Molecular Genetics from McFarland and colleagues describes the binding of Htt to the transcription factor MeCP2, using fluorescence lifetime imaging to measure Förster resonance energy transfer (FLIM-FRET).2 This report indicates that Htt binds to MeCP2, primarily in the nucleus. Binding of MeCP2 with Htt is enhanced in the presence of mHtt and may be involved in the change in BDNF levels that are characteristic of HD.
Another major theme in HD pathology is energetic defects due to mitochondrial dysfunction. Gouarné and colleagues report on mitochondrial respiratory function in different neuronal populations in a rat model of HD in their recent paper published in PLOS ONE.3 The oxygen consumption rate and extracellular acidification rate were reduced in striatal neurons, but not in cortical neurons in the presence of physiological factors, indicating a specific defect in glycolysis in the striatal neurons.
1 Mealer RG, Murray AJ, Shahani N, et al. Rhes, a striatal-selective protein implicated in Huntington disease, binds Beclin-1 and activates autophagy. J Biol Chem. 2013 Dec 9;doi:10.1074/jbc.M113.536912jbc.M113.536912.
2 McFarland KN, Huizenga MN, Darnell SB, et al. MeCP2: a novel Huntingtin interactor. Hum Mol Genet. 2013 Oct 18;doi: 10.1093/hmg/ddt499.
3 Gouarné C, Tardif G, Tracz J, et al. Early deficits in glycolysis are specific to striatal neurons from a rat model of Huntington disease. PLOS ONE. 2013 Nov 26; 8(11): e81528. doi:10.1371/journal.pone. 0081528.
Tetrabenazine (TBZ), a catecholaminedepleting agent first used for the treatment of schizophrenia, has great efficacy in hyperkinetic movement disorders. However, its mechanism of action remains incompletely understood. TBZ noncompetitively inhibits VMAT2, and Ugolev and colleagues recently uncovered additional mechanisms involved in the compound’s interaction with VMAT2.1 Using directed evolution and mutant isolation in yeast, the group found conserved glycine and proline residues that are required for TBZ binding, and found that the binding site for TBZ is distinct from the substrate binding site on VMAT2.
TBZ can cause parkinsonian symptoms due to a decrease in dopamine D2 Receptor transmission. A report by Podurgiel and colleagues in Neuroscience looks at tremulous jaw movements in rats, which are mimetic of parkinsonian tremor. The report aims to determine whether A2a antagonists could attenuate tremulous jaw movements induced by TBZ.2 The researchers found that MS3-X or A2a knockout attenuates tremulous jaw movements; therefore, an A2a inhibitor could be used in concert with TBZ as an anti-parkinsonian drug.
Shen and colleagues examined the long-term safety and efficacy of TBZ in an observational open-label study of 145 patients who were followed for one to 11 years. Patient response to TBZ did not vary based on the severity of chorea nor concomitant drug use. The most common adverse events reported were somnolence, insomnia, depression, accidental injury, and dysphagia. The study concluded that TBZ is nevertheless safe and effective for the treatment of chorea in HD patients.3
1 Ugolev Y, Segal T, Yaffe D, et al. Identification of conformationally sensitive residues essential for inhibition of vesicular monoamine transport by the noncompetitive inhibitor tetrabenazine. J Biol Chem. 2013 Sep 23; 288:32160-32171.
2 Podurgiel SJ, Nunes EJ, Yohn SE, et al. The vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine induces tremulous jaw movements in rodents: implications for pharmacological models of parkinsonian tremor. Neurosci. 2013 Oct 10;(250): 507-519.
3 Shen V, Clarence-Smith K, Hunter C, Jankovic, J. Safety and efficacy of tetrabenazine and use of concomitant medications during long-term, open-label treatment of chorea associated with Huntington’s and other diseases. Tremor Other Hyperkinet Mov. 2013 Oct 22; 3. pii: tre-03-191-4337-1.
Huntingtin (Htt) has important effects on the specific properties of nerve cells. Xu and colleagues designed an elegant mouse model that selectively expresses exon1 mutant Htt (mHtt) in synaptic terminals, achieved by tagging mHtt to SNAP25.1 Their results show that this model has age-dependent neurological symptoms of HD, and alterations in synaptic transmission. They also show that Htt can bind the polyproline-rich regions of synapsin-1. Alterations to this binding by mHtt may be responsible for pre-synaptic defects.
A recent paper published by Parsons and colleagues finds a presynaptic role of wildtype Htt.2 In the YAC18 mouse model there is an increase in the amount of synaptic PSD95, and the size of the PSD95 clusters in medium spiny neurons cocultured with cortical neurons. This effect was observed in medium spiny neurons even when only the cortical neurons were over-expressing Htt, indicating a presynaptic effect leading to alterations in PSD95. This increase in PSD95 clustering occurs concomitant with an increase in palmitoylation of PSD95, and requires the actions of brain-derived neurotrophic factor. Consequently, the effects of Htt on synaptic architecture need to be further studied, because Htt knockdown is currently a promising pharmacological approach for treatment of HD.
Finally, Wojtowicz and colleagues examine astrocytes, a currently understudied part of neuronal circuitry with respect to HD. They found that the release of nonsynaptic GABA from depolarized astrocytes, by the action of GAT-3, is strongly reduced in HD mice.3 This suggests that regulating GAT-3 may be a therapeutic target for HD symptoms.
1 Xu Q, Huang S, Song M, et al. Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms. J Cell Biol. 2013 Sep 30;202(7):1123-1138.
2 Parsons MP, Kang R, Buren C, et al. Bidirectional control of postsynaptic density-95 (PSD-95) clustering by huntingtin. J Biol Chem. 2013 Dec 17; doi: 10.1074/jbc.M113.513945jbc.M113.513945.
3 Wojtowicz AM, Dvorzhak A, Semtner M, Grantyn R. Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3. Front Neural Circuits. 2013 Nov 26; 7:188. doi: 10.3389/fncir.2013.00188.