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Intermediate alleles of HTT: A new pathway in longevity

      Highlights

      • Centenarians showed the highest HTT Intermediate alleles frequency compared to pathological and healthy controls.
      • Implication of HTT gene in longevity.
      • HTT Intermediate alleles may have a neuroprotective effect and a role in brain development.

      Abstract

      Centenarians are the best example of successful aging, reaching extreme longevity escaping age-related diseases. Genome sequencing studies provided evidence for genetic factors linked to heathy long life, including genes related to age-dependent diseases. HTT (Huntingtin) gene is linked to Huntington's Disease, but also associated to longevity in capuchins and mice. HTT Intermediate alleles (IAs) are defined as CAG repeat expansion between 27 and 35. According to recent data IAs might increase Alzheimer's Disease risk, but also might have a neuroprotective effect and can confer an advantage in brain development. Here, we investigated, for the first time, the possible implication of HTT IAs in extreme longevity and their possible association in cognitive decline. We analysed the distribution of IAs in Italian Centenarians (n = 143) and compared with pathological controls with cognitive decline (n = 232, including 80 Alzheimer's Disease, 78 Frontotemporal Dementia and 74 Subjective Cognitive Decline patients) and healthy controls (n = 104). Our data show a statistically significant higher frequency of IAs in Centenarians with respect to pathological controls with cognitive decline (p = .031; OR = 2.3097 95% CI 1.0591 to 5.0371), with a percentage of 11.2 respect to 5.4 respectively. The highest presence of IAs in Centenarians confirms and extends in humans a possible implication of HTT gene in exceptional lifespan and in brain development with a neuroprotective effect.

      Keywords

      Abbreviations:

      HTT (Huntingtin), IAs (Intermediate Alleles), ApoE (Apolipoprotein E), AD (Alzheimer's Disease), FTD (Frontotemporal Dementia), SCD (Subjective Cognitive Decline), HD (Huntington's Disease), PC (Pathological Controls), HC (Healthy Controls)
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      References

        • Gonos E.S.
        Genetics of aging: lessons from centenarians.
        Exp. Gerontol. 2000 Feb; 35 (PMID: 10705035): 15-21https://doi.org/10.1016/s0531-5565(99)00075-3
        • Montesanto A.
        • De Rango F.
        • Pirazzini C.
        • Guidarelli G.
        • Domma F.
        • Franceschi C.
        • Passarino G.
        Demographic, genetic and phenotypic characteristics of centenarians in Italy: focus on gender differences.
        Mech. Ageing Dev. 2017 Jul; 165 (Epub 2017 Apr 29. PMID: 28461103): 68-74https://doi.org/10.1016/j.mad.2017.04.008
        • Santos-Lozano A.
        • Santamarina A.
        • Pareja-Galeano H.
        • Sanchis-Gomar F.
        • Fiuza-Luces C.
        • Cristi-Montero C.
        • Bernal-Pino A.
        • Lucia A.
        • Garatachea N.
        The genetics of exceptional longevity: insights from centenarians.
        Maturitas. 2016 Aug; 90 (Epub 2016 May 10. PMID: 27282794): 49-57https://doi.org/10.1016/j.maturitas.2016.05.006
        • Caruso C.
        • Passarino G.
        • Puca A.
        • Scapagnini G.
        “Positive biology”: the centenarian lesson.
        Immun. Ageing. 2012; 9 (Published 2012 Apr 23)5
        • Willcox D.C.
        • Willcox B.J.
        • Hsueh W.C.
        • Suzuki M.
        Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study.
        Age (Dordr.). 2006 Dec; 28 (Epub 2006 Dec 8. PMID: 22253498; PMCID: PMC3259160): 313-332https://doi.org/10.1007/s11357-006-9020-x
        • Sebastiani P.
        • Perls T.T.
        The genetics of extreme longevity: lessons from the new England centenarian study.
        Front. Genet. 2012 Nov 30; 3 (PMID: 23226160; PMCID: PMC3510428): 277https://doi.org/10.3389/fgene.2012.00277
        • Garagnani P.
        • Marquis J.
        • Delledonne M.
        • Pirazzini C.
        • Marasco E.
        • Kwiatkowska K.M.
        • Iannuzzi V.
        • Bacalini M.G.
        • Valsesia A.
        • Carayol J.
        • Raymond F.
        • Ferrarini A.
        • Xumerle L.
        • Collino S.
        • Mari D.
        • Arosio B.
        • Casati M.
        • Ferri E.
        • Monti D.
        • Nacmias B.
        • Sorbi S.
        • Luiselli D.
        • Pettener D.
        • Castellani G.
        • Sala C.
        • Passarino G.
        • De Rango F.
        • D’Aquila P.
        • Bertamini L.
        • Martinelli N.
        • Girelli D.
        • Olivieri O.
        • Giuliani C.
        • Descombes P.
        • Franceschi C.
        Whole-genome sequencing analysis of semi-supercentenarians.
        Elife. 2021 May 4; 10 (PMID: 33941312; PMCID: PMC8096429)e57849https://doi.org/10.7554/eLife.57849
        • Broer L.
        • Buchman A.S.
        • Deelen J.
        • Evans D.S.
        • Faul J.D.
        • Lunetta K.L.
        • Sebastiani P.
        • Smith J.A.
        • Smith A.V.
        • Tanaka T.
        • Yu L.
        • Arnold A.M.
        • Aspelund T.
        • Benjamin E.J.
        • De Jager P.L.
        • Eirkisdottir G.
        • Evans D.A.
        • Garcia M.E.
        • Hofman A.
        • Kaplan R.C.
        • Kardia S.L.
        • Kiel D.P.
        • Oostra B.A.
        • Orwoll E.S.
        • Parimi N.
        • Psaty B.M.
        • Rivadeneira F.
        • Rotter J.I.
        • Seshadri S.
        • Singleton A.
        • Tiemeier H.
        • Uitterlinden A.G.
        • Zhao W.
        • Bandinelli S.
        • Bennett D.A.
        • Ferrucci L.
        • Gudnason V.
        • Harris T.B.
        • Karasik D.
        • Launer L.J.
        • Perls T.T.
        • Slagboom P.E.
        • Tranah G.J.
        • Weir D.R.
        • Newman A.B.
        • van Duijn C.M.
        • Murabito J.M.
        GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.
        J. Gerontol. A Biol. Sci. Med. Sci. 2015 Jan; 70 (Epub 2014 Sep 8. PMID: 25199915; PMCID: PMC4296168): 110-118https://doi.org/10.1093/gerona/glu166
        • Deelen J.
        • Beekman M.
        • Uh H.W.
        • Broer L.
        • Ayers K.L.
        • Tan Q.
        • Kamatani Y.
        • Bennet A.M.
        • Tamm R.
        • Trompet S.
        • Guðbjartsson D.F.
        • Flachsbart F.
        • Rose G.
        • Viktorin A.
        • Fischer K.
        • Nygaard M.
        • Cordell H.J.
        • Crocco P.
        • van den Akker E.B.
        • Böhringer S.
        • Helmer Q.
        • Nelson C.P.
        • Saunders G.I.
        • Alver M.
        • Andersen-Ranberg K.
        • Breen M.E.
        • van der Breggen R.
        • Caliebe A.
        • Capri M.
        • Cevenini E.
        • Collerton J.C.
        • Dato S.
        • Davies K.
        • Ford I.
        • Gampe J.
        • Garagnani P.
        • de Geus E.J.
        • Harrow J.
        • van Heemst D.
        • Heijmans B.T.
        • Heinsen F.A.
        • Hottenga J.J.
        • Hofman A.
        • Jeune B.
        • Jonsson P.V.
        • Lathrop M.
        • Lechner D.
        • Martin-Ruiz C.
        • Mcnerlan S.E.
        • Mihailov E.
        • Montesanto A.
        • Mooijaart S.P.
        • Murphy A.
        • Nohr E.A.
        • Paternoster L.
        • Postmus I.
        • Rivadeneira F.
        • Ross O.A.
        • Salvioli S.
        • Sattar N.
        • Schreiber S.
        • Stefánsson H.
        • Stott D.J.
        • Tiemeier H.
        • Uitterlinden A.G.
        • Westendorp R.G.
        • Willemsen G.
        • Samani N.J.
        • Galan P.
        • Sørensen T.I.
        • Boomsma D.I.
        • Jukema J.W.
        • Rea I.M.
        • Passarino G.
        • de Craen A.J.
        • Christensen K.
        • Nebel A.
        • Stefánsson K.
        • Metspalu A.
        • Magnusson P.
        • Blanché H.
        • Christiansen L.
        • Kirkwood T.B.
        • van Duijn C.M.
        • Franceschi C.
        • Houwing-Duistermaat J.J.
        • Slagboom P.E.
        Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.
        Hum. Mol. Genet. 2014 Aug 15; 23 (Epub 2014 Mar 31. PMID: 24688116; PMCID: PMC4103672): 4420-4432https://doi.org/10.1093/hmg/ddu139
        • Fortney K.
        • Dobriban E.
        • Garagnani P.
        • Pirazzini C.
        • Monti D.
        • Mari D.
        • Atzmon G.
        • Barzilai N.
        • Franceschi C.
        • Owen A.B.
        • Kim S.K.
        Genome-wide scan informed by age-related disease identifies loci for exceptional human longevity.
        PLoS Genet. 2015 Dec 17; 11 (PMID: 26677855; PMCID: PMC4683064)e1005728https://doi.org/10.1371/journal.pgen.1005728
        • Pilling L.C.
        • Atkins J.L.
        • Bowman K.
        • Jones S.E.
        • Tyrrell J.
        • Beaumont R.N.
        • Ruth K.S.
        • Tuke M.A.
        • Yaghootkar H.
        • Wood A.R.
        • Freathy R.M.
        • Murray A.
        • Weedon M.N.
        • Xue L.
        • Lunetta K.
        • Murabito J.M.
        • Harries L.W.
        • Robine J.M.
        • Brayne C.
        • Kuchel G.A.
        • Ferrucci L.
        • Frayling T.M.
        • Melzer D.
        Human longevity is influenced by many genetic variants: evidence from 75,000 UK biobank participants.
        Aging (Albany NY). 2016 Mar; 8: 547-560https://doi.org/10.18632/aging.100930. PMID: 27015805; PMCID: PMC4833145
        • Sebastiani P.
        • Bae H.
        • Sun F.X.
        • Andersen S.L.
        • Daw E.W.
        • Malovini A.
        • Kojima T.
        • Hirose N.
        • Schupf N.
        • Puca A.
        • Perls T.T.
        Meta-analysis of genetic variants associated with human exceptional longevity.
        Aging (Albany NY). 2013 Sep; 5: 653-661https://doi.org/10.18632/aging.100594. PMID: 24244950; PMCID: PMC3808698
        • Sebastiani P.
        • Gurinovich A.
        • Bae H.
        • Andersen S.
        • Malovini A.
        • Atzmon G.
        • Villa F.
        • Kraja A.T.
        • Ben-Avraham D.
        • Barzilai N.
        • Puca A.
        • Perls T.T.
        Four genome-wide association studies identify new extreme longevity variants.
        J. Gerontol. A Biol. Sci. Med. Sci. 2017 Oct 12; 72: 1453-1464https://doi.org/10.1093/gerona/glx027. PMID: 28329165; PMCID: PMC5861867
        • Cellini E.
        • Nacmias B.
        • Olivieri F.
        • Ortenzi L.
        • Tedde A.
        • Bagnoli S.
        • Petruzzi C.
        • Franceschi C.
        • Sorbi S.
        Cholesteryl ester transfer protein (CETP) I405V polymorphism and longevity in Italian centenarians.
        Mech. Ageing Dev. 2005; 126 (Jun–Jul. (PMID: 15888337)): 826-828https://doi.org/10.1016/j.mad.2005.01.009
        • Nacmias B.
        • Bagnoli S.
        • Tedde A.
        • Cellini E.
        • Bessi V.
        • Guarnieri B.
        • Ortensi L.
        • Piacentini S.
        • Bracco L.
        • Sorbi S.
        Angiotensin converting enzyme insertion/deletion polymorphism in sporadic and familial Alzheimer’s disease and longevity.
        Arch. Gerontol. Geriatr. 2007 Sep-Oct; 45 (Epub 2006 Dec 19): 201-206https://doi.org/10.1016/j.archger.2006.10.011
        17182125
        • Piaceri I.
        • Bagnoli S.
        • Lucenteforte E.
        • Mancuso M.
        • Tedde A.
        • Siciliano G.
        • Piacentini S.
        • Bracco L.
        • Sorbi S.
        • Nacmias B.
        Implication of a genetic variant at PICALM in Alzheimer’s disease patients and centenarians.
        J. Alzheimers Dis. 2011; 24 (PMID: 21297266): 409-413https://doi.org/10.3233/JAD-2011-101791
        • Orkin J.D.
        • Montague M.J.
        • Tejada-Martinez D.
        • de Manuel M.
        • Del Campo J.
        • Cheves Hernandez S.
        • Di Fiore A.
        • Fontsere C.
        • Hodgson J.A.
        • Janiak M.C.
        • Kuderna L.F.K.
        • Lizano E.
        • Martin M.P.
        • Niimura Y.
        • Perry G.H.
        • Valverde C.S.
        • Tang J.
        • Warren W.C.
        • de Magalhães J.P.
        • Kawamura S.
        • Marquès-Bonet T.
        • Krawetz R.
        • Melin A.D.
        The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fecalFACS.
        Proc. Natl. Acad. Sci. U. S. A. 2021 Feb 16; 118 (Erratum in: Proc Natl Acad Sci U S A. 2021 Aug 24;118(34): PMID: 33574059; PMCID: PMC7896301)e2010632118https://doi.org/10.1073/pnas.2010632118
        • Li Y.
        • de Magalhães J.P.
        Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity.
        Age (Dordr.). 2013 Apr; 35 (Epub 2011 Dec 29. PMID: 22205409; PMCID: PMC3592953): 301-314https://doi.org/10.1007/s11357-011-9361-y
        • Tacutu R.
        • Thornton D.
        • Johnson E.
        • Budovsky A.
        • Barardo D.
        • Craig T.
        • Diana E.
        • Lehmann G.
        • Toren D.
        • Wang J.
        • Fraifeld V.E.
        • de Magalhães J.P.
        Human ageing genomic resources: new and updated databases.
        Nucleic Acids Res. 2018 Jan 4; 46: D1083-D1090https://doi.org/10.1093/nar/gkx1042. PMID: 29121237; PMCID: PMC5753192
        • Zheng S.
        • Clabough E.B.
        • Sarkar S.
        • Futter M.
        • Rubinsztein D.C.
        • Zeitlin S.O.
        Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice.
        PLoS Genet. 2010; 6 (Published 2010 Feb 5): e1000838
      1. Chiu E. Huntington's disease. Burns A., Levy R. Dementia. Springer, Boston, MA. doi.1:0.1007/978-1-4615-6805-6_47.

        • De Luca A.
        • Morella A.
        • Consoli F.
        • Fanelli S.
        • Thibert J.R.
        • Statt S.
        • Latham G.J.
        • Squitieri F.
        A novel triplet-primed PCR assay to detect the full range of trinucleotide CAG repeats in the huntingtin gene (HTT).
        Int. J. Mol. Sci. 2021 Feb 8; 22 (PMID: 33567536; PMCID: PMC7916029): 1689https://doi.org/10.3390/ijms22041689
        • Cubo E.
        • Ramos-Arroyo M.A.
        • Martinez-Horta S.
        • Martínez-Descalls A.
        • Calvo S.
        • Gil-Polo C.
        • European HD Network
        Clinical manifestations of intermediate allele carriers in Huntington disease.
        Neurology. 2016 Aug 9; 87 (Epub 2016 Jul 8. PMID: 27402890): 571-578https://doi.org/10.1212/WNL.0000000000002944
        • Jot S.
        Parkinsonism with a hint of huntington’s from 29 CAG repeats in HTT.
        Brain Sci. 2019 Sep 22; 9 (PMID: 31546689; PMCID: PMC6826852): 245https://doi.org/10.3390/brainsci9100245
        • Savitt D.
        • Jankovic J.
        Clinical phenotype in carriers of intermediate alleles in the huntingtin gene.
        J. Neurol. Sci. 2019 Jul 15; 402 (Epub 2019 May 13. PMID: 31103960): 57-61https://doi.org/10.1016/j.jns.2019.05.010
        • Menéndez-González M.
        • Clarimón J.
        • Rosas-Allende I.
        • Blázquez M.
        • San Martín E.S.
        • García-Fernández C.
        • Lleó A.
        • Dols-Icardo O.
        • Illán-Gala I.
        • Morís G.
        • Ribacoba R.
        • Álvarez V.
        • Martínez C.
        HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer’s disease.
        Neurobiol. Aging. 2019 Apr; 76 (Epub 2018 Nov 28. PMID: 30583877): 215.e9-215.e14https://doi.org/10.1016/j.neurobiolaging.2018.11.014
        • McKhann G.M.
        • Knopman D.S.
        • Chertkow H.
        • Hyman B.T.
        • Jack Jr., C.R.
        • Kawas C.H.
        • Klunk W.E.
        • Koroshetz W.J.
        • Manly J.J.
        • Mayeux R.
        • Mohs R.C.
        • Morris J.C.
        • Rossor M.N.
        • Scheltens P.
        • Carrillo M.C.
        • Thies B.
        • Weintraub S.
        • Phelps C.H.
        The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.
        Alzheimers Dement. 2011 May; 7 (Epub 2011 Apr 21. PMID: 21514250; PMCID: PMC3312024): 263-269https://doi.org/10.1016/j.jalz.2011.03.005
        • Rascovsky K.
        • Hodges J.R.
        • Knopman D.
        • Mendez M.F.
        • Kramer J.H.
        • Neuhaus J.
        • van Swieten J.C.
        • Seelaar H.
        • Dopper E.G.
        • Onyike C.U.
        • Hillis A.E.
        • Josephs K.A.
        • Boeve B.F.
        • Kertesz A.
        • Seeley W.W.
        • Rankin K.P.
        • Johnson J.K.
        • Gorno-Tempini M.L.
        • Rosen H.
        • Prioleau-Latham C.E.
        • Lee A.
        • Kipps C.M.
        • Lillo P.
        • Piguet O.
        • Rohrer J.D.
        • Rossor M.N.
        • Warren J.D.
        • Fox N.C.
        • Galasko D.
        • Salmon D.P.
        • Black S.E.
        • Mesulam M.
        • Weintraub S.
        • Dickerson B.C.
        • Diehl-Schmid J.
        • Pasquier F.
        • Deramecourt V.
        • Lebert F.
        • Pijnenburg Y.
        • Chow T.W.
        • Manes F.
        • Grafman J.
        • Cappa S.F.
        • Freedman M.
        • Grossman M.
        • Miller B.L.
        Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.
        Brain. 2011 Sep; 134 (Epub 2011 Aug 2. PMID: 21810890; PMCID: PMC3170532): 2456-2477https://doi.org/10.1093/brain/awr179
        • Jessen F.
        • Amariglio R.E.
        • van Boxtel M.
        • Breteler M.
        • Ceccaldi M.
        • Chételat G.
        • Dubois B.
        • Dufouil C.
        • Ellis K.A.
        • van der Flier W.M.
        • Glodzik L.
        • van Harten A.C.
        • de Leon M.J.
        • McHugh P.
        • Mielke M.M.
        • Molinuevo J.L.
        • Mosconi L.
        • Osorio R.S.
        • Perrotin A.
        • Petersen R.C.
        • Rabin L.A.
        • Rami L.
        • Reisberg B.
        • Rentz D.M.
        • Sachdev P.S.
        • de la Sayette V.
        • Saykin A.J.
        • Scheltens P.
        • Shulman M.B.
        • Slavin M.J.
        • Sperling R.A.
        • Stewart R.
        • Uspenskaya O.
        • Vellas B.
        • Visser P.J.
        • Wagner M.
        • Subjective Cognitive Decline Initiative (SCD-I) Working Group
        A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease.
        Alzheimers Dement. 2014 Nov; 10 (Epub 2014 May 3. PMID: 24798886; PMCID: PMC4317324): 844-852https://doi.org/10.1016/j.jalz.2014.01.001
        • Jama M.
        • Millson A.
        • Miller C.E.
        • Lyon E.
        Triplet repeat primed PCR simplifies testing for Huntington disease.
        J. Mol. Diagn. 2013 Mar; 15 (Epub 2013 Feb 13. PMID: 23414820): 255-262https://doi.org/10.1016/j.jmoldx.2012.09.005
        • Sorbi S.
        • Nacmias B.
        • Forleo P.
        • Latorraca S.
        • Gobbini I.
        • Bracco L.
        • Piacentini S.
        • Amaducci L.
        ApoE allele frequencies in Italian sporadic and familial Alzheimer’s disease.
        Neurosci. Lett. 1994 Aug 15; 177 (PMID: 7824157): 100-102https://doi.org/10.1016/0304-3940(94)90054-x
        • Tindale L.C.
        • Leach S.
        • Ushey K.
        • Daley D.
        • Brooks-Wilson A.R.
        Rare and common variants in the apolipoprotein E gene in healthy oldest old.
        Neurobiol. Aging. 2014 Mar; 35 (727.e1–3. Epub 2013 Oct 11. PMID: 24126160)https://doi.org/10.1016/j.neurobiolaging.2013.09.010
        • Lee J.K.
        • Ding Y.
        • Conrad A.L.
        • Cattaneo E.
        • Epping E.
        • Mathews K.
        • Gonzalez-Alegre P.
        • Cahill L.
        • Magnotta V.
        • Schlaggar B.L.
        • Perlmutter J.S.
        • Kim R.E.
        • Dawson J.D.
        • Nopoulos P.
        Sex-specific effects of the Huntington gene on normal neurodevelopment.
        J. Neurosci. Res. 2017 Jan 2; 95 (PMID: 27870408; PMCID: PMC5729280): 398-408https://doi.org/10.1002/jnr.23980
        • Zuchner T.
        • Brundin P.
        Mutant huntingtin can paradoxically protect neurons from death.
        Cell Death Differ. 2008; 15: 435-442https://doi.org/10.1038/sj.cdd.4402261
        • Aman Y.
        • Schmauck-Medina T.
        • Hansen M.
        • Morimoto R.I.
        • Simon A.K.
        • Bjedov I.
        • Palikaras K.
        • Simonsen A.
        • Johansen T.
        • Tavernarakis N.
        • Rubinsztein D.C.
        • Partridge L.
        • Kroemer G.
        • Labbadia J.
        • Fang E.F.
        Autophagy in healthy aging and disease.
        Nat. Aging. 2021 Aug; 1 (Epub 2021 Aug 12. PMID: 34901876; PMCID: PMC8659158): 634-650https://doi.org/10.1038/s43587-021-00098-4
        • Hansen M.
        • Chandra A.
        • Mitic L.L.
        • Onken B.
        • Driscoll M.
        • Kenyon C.
        A role for autophagy in the extension of lifespan by dietary restriction in C. elegans.
        PLoS Genet. 2008 Feb; 4 (e24. PMID: 18282106; PMCID: PMC2242811)https://doi.org/10.1371/journal.pgen.0040024
        • Barbosa M.C.
        • Grosso R.A.
        • Fader C.M.
        Hallmarks of aging: an autophagic perspective.
        Front. Endocrinol. (Lausanne). 2019 Jan 9; 9: 790https://doi.org/10.3389/fendo.2018.00790. PMID: 30687233; PMCID: PMC6333684
        • Kaushik S.
        • Tasset I.
        • Arias E.
        • Pampliega O.
        • Wong E.
        • Martinez-Vicente M.
        • Cuervo A.M.
        Autophagy and the hallmarks of aging.
        Ageing Res. Rev. 2021 Dec; 72 (Epub 2021 Sep 24. PMID: 34563704; PMCID: PMC8616816): 101468https://doi.org/10.1016/j.arr.2021.101468
        • Stead E.R.
        • Castillo-Quan J.I.
        • Miguel V.E.M.
        • Lujan C.
        • Ketteler R.
        • Kinghorn K.J.
        • Bjedov I.
        Agephagy - adapting autophagy for health during aging.
        Front. Cell. Dev. Biol. 2019 Nov 28; 7 (PMID: 31850344; PMCID: PMC6892982): 308https://doi.org/10.3389/fcell.2019.00308
        • Cattaneo E.
        • Zuccato C.
        • Tartari M.
        Normal huntingtin function: an alternative approach to Huntington’s disease.
        Nat. Rev. Neurosci. 2005; 6: 919-930
        • Schaefer M.H.
        • Wanker E.E.
        • Andrade-Navarro M.A.
        Evolution and function of CAG/polyglutamine repeats in protein-protein interaction networks.
        Nucleic Acids Res. 2012; 40: 4273-4287
        • Caron N.S.
        • Desmond C.R.
        • Xia J.
        • Truant R.
        Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin.
        Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 14610-14615
        • Bessi V.
        • Mazzeo S.
        • Bagnoli S.
        • Giacomucci G.
        • Ingannato A.
        • Ferrari C.
        • Padiglioni S.
        • Franchi V.
        • Sorbi S.
        • Nacmias B.
        The effect of CAG repeats within the non-pathological range in the HTT gene on cognitive functions in patients with subjective cognitive decline and mild cognitive impairment.
        Diagnostics (Basel). 2021 Jun 7; 11 (PMID: 34200421; PMCID: PMC8228729): 1051https://doi.org/10.3390/diagnostics11061051