Kendahl Lyle

Introduction. Huntington’s disease is an autosomal dominant disease due to a CAG trinucleotide repeat on chromosome 4 and the greater number of repeats corresponds to an earlier onset of symptoms.¹ Huntington’s disease has a prevalence of 10.6-13.7 per 100,000 in western populations, and females are shown to have a faster progression with worse motor symptoms.^2,3 The three main categories of symptoms seen are chorea movements, cognitive disturbances, and psychiatric problems brought about by the mutant Huntingtin protein (mHTT) impairing mitochondrial function and increasing ROS.^1,4 Melatonin is an endogenous amphiphilic hormone secreted by the pineal gland and observed to be decreased in Huntington’s patients.⁵ The decrease in serum melatonin corresponds with a decrease in melatonin receptor 1A (MT1), making neurons more susceptible to cell death in Huntington’s disease.⁵  Methods. The hydrophilic melatonin receptor ligand ICOA-13 was derived from a lipophilic precursor by tagging with the hydrophilic Cy3 cyanin fluorophore.⁶ Fluorometric protease assay kit was utilized to determine cytochrome c release between aralkylamine N-acetyltransferase knockout (AANAT-KO) and mouse neuroblastoma (N2a) cells, while 4P-PDOT, an MT2 antagonist, was used to validate MT1 mediation.⁷ Control and HD sheep (rams and ewes) were obtained from the South Australian Research and Development Institute.⁸ Mouse models included C57/BL6 wild type, MT1 knockout, AANAT-KO, and R6/2.^9,10  Results. ICOA-13 displayed a significant difference between G inhibitory cAMP signaling at the cell plasma membrane and neuronal mitochondria for the MT1 receptor compared to melatonin.⁶ Melatonin is synthesized in neuronal mitochondria where it then acts on the MT1/GPCR signal transduction pathway to inhibit cytochrome c release, downstream caspase activation, and neurodegenerative progression.⁷ Melatonin reduced brain damage, inhibited mitochondrial-mediated cell death through MT1, and inhibited cytochrome c release.⁹ There was a statistically significant increase in plasma melatonin levels and melatonin production in pre-symptomatic Huntington’s sheep compared to the control.⁸ Exogenous melatonin attenuated neuroinflammation by decreasing the release of ROS, mtDNA, and levels of cGAS/STING/IRF3 from neuronal mitochondria.¹⁰  Conclusions. The theoretical mechanistic model based on this research explains that, in the pre-symptomatic stage, an upregulation of melatonin and MT1 prevents mHTT from disrupting the OMM and releasing mtDNA and cytochrome c in the cytosol.^7-9 Then, at symptomatic onset, downregulation of melatonin and MT1 leads to disruption of the OMM and release of these neurotoxic materials.^5,7,9 Disease progresses with increasing mtDNA and cytochrome c release triggering neuroinflammation and apoptosis respectively.^7,10

1. Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb Perspect Med. Jul 5 2017;7(7)doi:10.1101/cshperspect.a024240
2. Ullah MF, Ahmad A, Bhat SH, Abu-Duhier FM, Barreto GE, Ashraf GM. Impact of sex differences and gender specificity on behavioral characteristics and pathophysiology of neurodegenerative disorders. Neurosci Biobehav Rev. Jul 2019;102:95-105. doi:10.1016/j.neubiorev.2019.04.003
3. McColgan P, Tabrizi SJ. Huntington’s disease: a clinical review. Eur J Neurol. Jan 2018;25(1):24-34. doi:10.1111/ene.13413
4. Wyant KJ, Ridder AJ, Dayalu P. Huntington’s Disease-Update on Treatments. Curr Neurol Neurosci Rep. Apr 2017;17(4):33. doi:10.1007/s11910-017-0739-9
5. Wang X, Sirianni A, Pei Z, et al. The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J Neurosci. Oct 12 2011;31(41):14496-507. doi:10.1523/jneurosci.3059-11.2011
6. Gbahou F, Cecon E, Viault G, et al. Design and validation of the first cell-impermeant melatonin receptor agonist. Br J Pharmacol. Jul 2017;174(14):2409-2421. doi:10.1111/bph.13856
7. Suofu Y, Li W, Jean-Alphonse FG, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci U S A. Sep 19 2017;114(38):E7997-e8006. doi:10.1073/pnas.1705768114
8. Morton AJ, Middleton B, Rudiger S, Bawden CS, Kuchel TR, Skene DJ. Increased plasma melatonin in presymptomatic Huntington disease sheep (Ovis aries): Compensatory neuroprotection in a neurodegenerative disease? J Pineal Res. Mar 2020;68(2):e12624. doi:10.1111/jpi.12624
9. Sinha B, Wu Q, Li W, et al. Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor. J Pineal Res. Jan 2018;64(1)doi:10.1111/jpi.12443
10. Jauhari A, Baranov SV, Suofu Y, et al. Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J Clin Invest. Jun 1 2020;130(6):3124-3136. doi:10.1172/jci135026