Relevancia de componentes del eje hipotálamo-hipófisis-gonadal en la fisiopatología de proteinopatías del sistema nervioso

Kenia Hechevarría Bárzaga, Raúl Aguilera Rodríguez, Dennis Almaguer Gotay, Amarilis Álvarez Sosa, Luis Enrique Almaguer Mederos

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Resumen

Introducción: Varias proteinopatías del sistema nervioso están asociadas a la ocurrencia de alteraciones en componentes del eje hipotálamo-hipófisis-gonadal.

Objetivo: Reflejar la relevancia de componentes del eje hipotálamo-hipófisis-gonadal en la fisiopatología de proteinopatías del sistema nervioso.

Material y Métodos: Se realizó una revisión bibliográfica durante los meses de enero de 2018 a diciembre de 2018. Fueron consultadas bases de datos de referencia, con el uso de descriptores y operadores booleanos. La estrategia de búsqueda avanzada para la selección de los artículos fue empleada, teniendo en cuenta la calidad metodológica o validez de los estudios.

Desarrollo: Fueron identificaron alteraciones del funcionamiento normal del eje hipotálamo-hipófisis-gonadal en varias proteinopatías del sistema nervioso. Las alteraciones más frecuentemente reportadas fueron el incremento en los niveles de gonadotropinas, principalmente de la hormona luteinizante, en la enfermedad de Alzheimer, y la disminución de los niveles de testosterona en las enfermedades de Alzheimer, Parkinson, Huntington y Esclerosis Lateral Amiotrófica, con el consiguiente agravamiento del fenotipo clínico. Se obtuvieron evidencias de naturaleza preliminar, que fundamentan la posible ocurrencia de disfunción hipotalámica en pacientes con Ataxias espinocerebelosas.

Conclusiones: Aun cuando existen evidencias que demuestran la existencia de un vínculo entre la fisiopatología de proteinopatías del sistema nervioso y alteraciones en componentes del eje hipotálamo-hipófisis-gonadal, se requerirán estudios más extensos e integrales para confirmar estas asociaciones y para caracterizar los mecanismos moleculares implicados.

Palabras clave

enfermedades del sistema nervioso, hormona folículo estimulante, hormona luteinizante, sistema hipotálamo-hipofisário, testosterona

Referencias

Scannevin RH. Therapeutic strategies for targeting neurodegenerative protein misfolding disorders. Current Opinion in Chemical Biology 2018; 44:66-74.

Khanam H, Ali A, Asif M, Shamsuzzaman. Neurodegenerative diseases linked to misfolded proteins and their therapeutic approaches: A review. Eur J Med Chem. 2016; 124:1121-1141.

Ugalde CL, Finkelstein DI, Lawson VA, Hill AF. Pathogenic mechanisms of prion protein, amyloid-β and α-synuclein misfolding: the prion concept and neurotoxicity of protein oligomers. J Neurochem. 2016; 139(2):162-180.

Kawamata H, Manfredi G. Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases. J Cell Biol. 2017; 216(12):3917-3929.

St-Amour I, Turgeon A, Goupil C, Planel E, Hébert SS. Co-occurrence of mixed proteinopathies in late-stage Huntington's disease. Acta Neuropathol. 2018; 135(2):249-265.

De Pablo-Fernandez E, Courtney R, Holton JL, Warner TT. Hypothalamic α-synuclein and its relation to weight loss and autonomic symptoms in Parkinson's disease. Mov Disord. 2017; 32(2):296-298.

Bellosta-Diago E, Viloria-Alebesque A, Santos-Lasaosa S, Lopez Del Val LJ. The hypothalamus in Huntington's disease. Rev Neurol. 2017; 65(9):415-422.

Bhatia E, Shukla R, Gupta RK, Misra UK. Multiple pituitary hormone deficiencies in apatient with spinocerebellar ataxia: Magnetic resonance imaging and hormonal studies. J. Endocrinol. Invest. 1993; 16: 639-642.

Libro R, Bramanti P, Mazzon E. Endogenous glucocorticoids: role in the etiopathogenesis of Alzheimer's disease. Neuro Endocrinol Lett. 2017; 38(1):1-12.

Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OFX, Sousa N, et al. Chronic stress and glucocorticoids: from neuronal plasticity to neurodegeneration. Neural Plasticity 2016; 1-15.

Bartlett DM, Cruickshank TM, Hannan AJ, Eastwood PR, Lazar AS, Ziman MR. Neuroendocrine and neurotrophic signaling in Huntington's disease: Implications for pathogenic mechanisms and treatment strategies. Neurosci Biobehav Rev. 2016; 71:444-454.

Penke B, Bogár F, Fülöp L. Protein Folding and Misfolding, Endoplasmic Reticulum Stress in Neurodegenerative Diseases: in Trace of Novel Drug Targets. Curr Protein Pept Sci. 2016; 17(2):169-82.

Elfawy HA, Das B. Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: Etiologies and therapeutic strategies. Life Sci. 2018; S0024-3205(18)30822-1.

Hekmatimoghaddam S, Zare-Khormizi MR, Pourrajab F. Underlying mechanisms and chemical/biochemical therapeutic approaches to ameliorate protein misfolding neurodegenerative diseases. Biofactors 2017; 43(6):737-759.

Sweeney P, Park H, Baumann M, Dunlop J, Frydman J, Kopito R, et al. Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener. 2017; 6:6.

Bayer TA. Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders? Eur Neuropsychopharmacol. 2015; 25(5):713-24.

Ling H. Untangling the tauopathies: Current concepts of tau pathology and neurodegeneration. Parkinsonism Relat Disord. 2018; 46 Suppl 1:S34-S38.

Ciechanover A, Kwon YT. Protein quality control by molecular chaperones in neurodegeneration. Front Neurosci. 2017; 11:185.

Paulson HL, Shakkottai VG, Clark HB, Orr HT. Polyglutamine spinocerebellar ataxias- from genes to potential treatments. Nat Rev Neurosci. 2017; 18(10):613-626.

Stoyas CA, La Spada AR. The CAG-polyglutamine repeat diseases: a clinical, molecular, genetic, and pathophysiologic nosology. Handb Clin Neurol. 2018; 147:143-170.

Bowen RL, Isley JP, Atkinson RL. An association of elevated serum gonadotropin concentrations and Alzheimer disease? J Neuroendocrinol 2000; 12: 351-354.

Short RA, Bowen RL, O’Brien PC, Graff-Radford NR. Elevated gonadotropin levels in patients with Alzheimer disease. Mayo Clin Proc 2001; 76: 906-909.

Okun MS, Wu SS, Jennings D, Marek K, Rodriguez RL, Fernandez HH. Testosterone level and the effect of levodopa and agonists in early Parkinson disease: results from the INSPECT cohort. Journal of Clinical Movement Disorders 2014; 1:8.

Gargiulo MG, Meyer M, Rodríguez GE, Garay LI, Sica REP, De Nicola AF, et al. Endogenous progesterone is associated to amyotrophic lateral sclerosis prognostic factors. ActaNeurol Scand. 2011; 123: 60-67.

Saleh N, Moutereau S, Durr A, Krystkowiak P, Azulay J-P, Tranchant C, et al. Neuroendocrine Disturbances in Huntington’s Disease. PLoS ONE 2009; 4(3): e4962.

Kalliolia E, Silajdžić E, Nambron R, Costelloe SJ, Martin NG, Hill NR, et al. A 24-hour study of the hypothalamo-pituitary axes in Huntington’s disease. PLoS ONE 2015; 10(10): e0138848.

Berciano J, Amado JA, Freijanes J, Rebello M, Vaquero A. Familial cerebellar ataxia and hypogonadotrophic hypogonadism: evidence for hypothalamic LHRH deficiency. J Neurol. Neurosurg. Psychiatry 1982; 45: 747.

Fok AC, Wong ME, Cheah J. Syndrome of cerebellar ataxia and hypogonadotropic hypogonadism: evidence of pituitary gonadotropin deficiency. J NeurolNeurosurg Psychiatry 1989; 52: 407.

Blair JA, McGee H, Bhatta S, Palm R, Casadesus G. Hypothalamic–pituitary–gonadal axis involvement in learning and memory and Alzheimer’s disease: more than “just” estrogen. Frontiers in Endocrinology 2015a; 6: 45.

Rao CV. There is no turning back on the paradigm shift on the actions of human chorionic gonadotropin and luteinizing hormone. J Reprod Health and Med. 2016; 2:4-10.

Acevedo-Rodriguez A, Kauffman AS, Cherrington BD, Borges CS, Roepke TA, Laconi M. Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. J Neuroendocrinol. 2018; 30(10):e12590.

Andreasson K, Worley PF. Induction of beta-Activin expression by synaptic activity and during neocortical development. Neuroscience 1995; 69: 781-796.

Pino A, Fumagalli G, Bifari F, Decimo I. New neurons in adult brain: distribution, molecular mechanisms and therapies. Biochem Pharmacol. 2017; 141:4-22.

Blair JA, Bhatta S, McGee H, Casadesus G. Luteinizing Hormone: Evidence for direct action in the CNS. Horm Behav. 2015b; 76: 57-62.

Celec P, Ostatníková D, Hodosy J. On the effects of testosterone on brain behavioral functions. Front Neurosci. 2015; 9:12.

Hines M, Spencer D, Kung KT, Browne WV, Constantinescu M, Noorderhaven RM. The early postnatal period, mini-puberty, provides a window on the role of testosterone in human neurobehavioural development. Curr Opin Neurobiol. 2016; 38:69-73.

Siddiqui AN, Siddiqui N, Khan RA, Kalam A, Jabir NR, Kamal MA, et al. Neuroprotective Role of Steroidal Sex Hormones: An Overview. CNS NeurosciTher. 2016; 22(5):342-50.

Mendell AL, MacLusky NJ. Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection: Implications for Sex Differences in Neurodegenerative Disease. Front Mol Neurosci. 2018; 11:359.

Brotfain E, Gruenbaum SE, Boyko M, Kutz R, Zlotnik A, Klein M. Neuroprotection by Estrogen and Progesterone in Traumatic Brain Injury and Spinal Cord Injury. Curr Neuropharmacol. 2016; 14(6):641-53.

Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388:1545-1602.

Chatani E, Yamamoto N. Recent progress on understanding the mechanisms of amyloid nucleation. Biophys Rev 2018; 10:527-534.

Metaxas A, Kempf SJ. Neurofibrillary tangles in Alzheimer's disease: elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics. Neural Regen Res. 2016; 11(10):1579-1581.

Al-Hader AA, Lei ZM, Rao CN. Novel expression of functional luteinizing hormone/chorionic gonadotropin receptors in cultured glial cells from neonatal rat brains. BiolReprod 1997; 56: 501-507.

Lukacs H, Hiatt ES, Lei ZM, Rao CV. Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats. HormBehav 1995; 29: 42-58.

Webber KM, Bowen R, Casadesus G, Perry G, Atwood CS, Smith MA. Gonadotropins and Alzheimer’s disease: the link between estrogen replacement therapy and neuroprotection. Acta Neurobiol Exp 2004; 64:113-118.

Bowen RL, Smith MA, Harris PLR, Kubat Z, Martins RN, Castellani RJ, et al. Elevated luteinizing hormone expression colocalizes with neurons vulnerable to alzheimer’s disease pathology. J Neurosci Res 2002; 70: 514-518.

Bowen RL, Verdile G, Liu T, Parlow AF, Perry G, Smith MA, et al. Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-b precursor protein and amyloid-b deposition. J Biol Chem. 2004; 279(19):20539-20545.

Ogawa O, Lee HG, Zhu X, Raina A, Harris PL, Castellani RJ, et al. Increased p27, an essential component of cell cycle control, in Alzheimer’s disease. Aging Cell 2003; 2:105-110.

Saberi S, Du YP, Christie M, Goldsburry C. Human chorionic gonadotropin increases b-cleavage of amyloid precursor protein in SH-SY5Y cells. Cell MolNeurobiol. 2013; 33(6):747-751.

Burnham VL, Thornton JE. Luteinizing hormone as a key player in the cognitive decline of Alzheimer’s disease. HormBehav. 2015; 76:48-56.

Okun MS, DeLong MR, Hanfelt J, Gearing M, Levey A. Plasma testosterone levels in Alzheimer and Parkinson diseases. Neurology 2004; 62:411-413.

Verdile G, Laws SM, Henley D, Ames D, Al Bush, Ellis KA, et al. Associations between gonadotropins, testosterone and β-amyloid in men at risk of Alzheimer’s disease. Molecular Psychiatry 2014; 19:69-75.

Gouras GK, Xu H, Gross RS, Greenfield JP, Hai B, Wang R, et al. Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci USA. 2000; 97(3):1202-1205.

Hogervorst E, Bandelow S, Combrinck M, Smith AD. Low free testosterone is an independent risk factor for Alzheimer’s disease. Exp Gerontol. 2004; 39:1633-1639.

Cacabelos R. Parkinson's Disease: From Pathogenesis to Pharmacogenomics. Int J Mol Sci. 2017; 18(3).

Rocha EM, De Miranda B, Sanders LH. Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis 2018; 109:249-257.

Okun MS, Walter BL, McDonald WM, Tenover JL, Green J, Juncos JL, DeLong MR. Beneficial effects of testosterone replacement for the nonmotor symptoms of Parkinson disease. Arch Neurol 2002; 59:(11)1750-1753.

Okun MS, Fernandez HH, Rodriguez RL, Romrell J, Suelter M, Munson S, et al. Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study. Arch Neurol 2006; 63:(5)729-735.

Chou KL, Moro-De-Casillas ML, Amick MM, Borek LL, Friedman JH. Testosterone not associated with violent dreams or REM sleep behavior disorder in men with Parkinson’s. MovDisord 2007; 22:411-414.

Mitchell E, Thomas D, Burnet R. Testosterone improves motor function in Parkinson’s disease. J ClinNeurosci 2006; 13:133-136.

Braak H, Del Tredici K. Neuropathological Staging of Brain Pathology in Sporadic Parkinson's disease: Separating the Wheat from the Chaff. J Parkinsons Dis. 2017; 7(s1):S71-S85.

Garrido A, Aldecoa I, Gelpi E, Tolosa E. Aggregation of α-Synuclein in the gonadal tissue of 2 patients with Parkinson disease. JAMA Neurol. 2017; 74(5):606-607.

Brown RH, Phil D, Al­Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med 2017; 377:162-72.

Cykowski MD, Powell SZ, Peterson LE, Appel JW, Rivera AL, Takei H, et al. Clinical significance of TDP-43 neuropathology in Amyotrophic Lateral Sclerosis. J Neuropathol Exp Neurol. 2017; 76(5):402-413.

Militello A, Vitello G, Lunetta C, Toscano A, Maiorana G, Piccoli T, et al. The serum level of free testosterone is reduced in amyotrophic lateral sclerosis. J Neurol Sci. 2002; 195(1):67-70.

Fargo KN, Foster AM, Sengelaub DR. Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons. Dev Neurobiol. 2009; 69(12):825-35.

Little CM, Coons KD, Sengelaub DR. Neuroprotective effects of testosterone on the morphology andfunction of somatic motoneurons following the death of neighboring motoneurons. J CompNeurol. 2009; 512:359-372.

McColgan P, Tabrizi SJ. Huntington's disease: a clinical review. Eur J Neurol. 2018; 25(1):24-34.

Pircs K, Petri R, Madsen S, Brattås PL, Vuono R, Ottosson DR, et al. Huntingtin aggregation impairs autophagy, leading to Argonaute-2 accumulation and global microRNA dysregulation. Cell Rep. 2018; 24(6):1397-1406.

Papalexi E, Persson A, Bjorkqvist M, Petersen A, Woodman B, Bates GP, et al. Reduction ofGnRH and infertility in the R6/2 mouse model of Huntington's disease. Eur J Neurosci 2005; 22: 1541-1546.

Van Raamsdonk JM, Murphy Z, Selva DM, Hamidizadeh R, Pearson J, Petersen A, et al. Testicular degeneration in Huntington disease. Neurobiol Dis 2007; 26: 512-520.

Markianos M, Panas M, Kalfakis N, Vassilopoulos D. Plasma testosterone in male patients with Huntington’s disease: relations to severity of illness and dementia. Ann Neurol. 2005; 57:520-525.

Ashizawa T, Öz G, Paulson HL. Spinocerebellar ataxias: prospects and challenges for therapy development. Nat Rev Neurol. 2018; 14(10):590-605.



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