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Cited by 146Genetic Neurodegenerative DiseasesLysosomal Storage Disorders ResearchAlzheimer's disease research and treatments

Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis

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Wang, Guohao, Liu, Xudong, Gaertig, Marta A., Li, Shihua, Li, Xiao-Jiang·2016·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1524575113PMC PMC4812735
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Abstract

Significance: Because of the toxicity gain of expanded polyglutamine (polyQ) repeats, many studies have used RNAi and other approaches to inactivate the mutant HTT gene in Huntington’s disease. However, Htt is essential for early embryonic development, and normal function of Htt in adult animals remains unknown. Using conditional Htt knockout mice, we found that loss of Htt causes the lethal phenotype only in postnatal mice but not in adult mice, and this early death is due to acute pancreatitis. Htt interacts with serine protease inhibitor Kazal-type 3 (Spink3) to inhibit trypsin activity in pancreatic cells and thus prevents acinar cell degeneration and pancreatitis. This age- and cell type-dependent function indicates the safety in knocking down neuronal HTT in adult brains for treating Huntington’s disease.

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  • Our findings are consistent with published data in adult mice demonstrating that eliminating HTT causes minimal off-target phenotypes.

    “our findings are consistent with published data in adult mice demonstrating that eliminating HTT causes minimal off-target phenotypes48”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [48]

    The Discussion (page unavailable) reports no significant movement or behavioral phenotypes after Htt knockout in adult neurons, supporting the claim for brain-targeted elimination. The ‘Loss of Htt Mediates Age-Dependent Death in Mice’ section (page unavailable) also reports that 95% of mice depleted at eight months survived, but only 70% of those depleted at four months survived. Thus, ‘minimal off-target phenotypes’ overgeneralizes the findings across adult mice and depletion conditions. (LLM, conf=0.85)

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  1. Ross CA, et al. (2014) Huntington disease: Natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10(4):204-216.
  2. Di Paola M, et al. (2014) MRI measures of corpus callosum iron and myelin in early Huntington's disease. Hum Brain Mapp 35(7):3143-3151.
  3. Stoffers D, et al. (2010) Contrasting gray and white matter changes in preclinical Huntington disease: An MRI study. Neurology 74(15):1208-1216.
  4. Nasir J, et al. (1995) Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81(5):811-823.
  5. Duyao MP, et al. (1995) Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269(5222):407-410.
  6. Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A (1995) Increased apo- ptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat Genet 11(2):155-163.
  7. Heng MY, Detloff PJ, Albin RL (2008) Rodent genetic models of Huntington disease. Neurobiol Dis 32(1):1-9.
  8. Lee JM, et al. (2013) Dominant effects of the Huntington's disease HTT CAG repeat length are captured in gene-expression data sets by a continuous analysis mathe- matical modeling strategy. Hum Mol Genet 22(16):3227-3238.
  9. Crook ZR, Housman D (2011) Huntington's disease: Can mice lead the way to treat- ment? Neuron 69(3):423-435.
  10. Yang D, et al. (2010) Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet 19(20):3983-3994.
  11. Xu Q, et al. (2013) Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms. J Cell Biol 202(7):1123-1138.
  12. Southwell AL, Patterson PH (2011) Gene therapy in mouse models of huntington disease. Neuroscientist 17(2):153-162.
  13. Zhang Y, Friedlander RM (2011) Using non-coding small RNAs to develop therapies for Huntington's disease. Gene Ther 18(12):1139-1149.
  14. Aronin N, DiFiglia M (2014) Huntingtin-lowering strategies in Huntington's disease: Antisense oligonucleotides, small RNAs, and gene editing. Mov Disord 29(11):1455-1461.
  15. Dragatsis I, Levine MS, Zeitlin S (2000) Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 26(3):300-306.
  16. White JK, et al. (1997) Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat Genet 17(4):404-410.
  17. Hashimoto D, et al. (2008) Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells. J Cell Biol 181(7):1065-1072.
  18. Gaisano HY, Gorelick FS (2009) New insights into the mechanisms of pancreatitis. Gastroenterology 136(7):2040-2044.
  19. Sah RP, Dawra RK, Saluja AK (2013) New insights into the pathogenesis of pancrea- titis. Curr Opin Gastroenterol 29(5):523-530.
  20. Hegyi P, Rakonczay Z (2010) Insufficiency of electrolyte and fluid secretion by pan- creatic ductal cells leads to increased patient risk for pancreatitis. Am J Gastroenterol 105(9):2119-2120.
  21. Ohmuraya M, Hirota M, Araki K, Baba H, Yamamura K (2006) Enhanced trypsin ac- tivity in pancreatic acinar cells deficient for serine protease inhibitor kazal type 3. Pancreas 33(1):104-106.
  22. Noone PG, et al. (2001) Cystic fibrosis gene mutations and pancreatitis risk: Relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 121(6):1310-1319.
  23. Witt H, et al. (2000) Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 25(2):213-216.
  24. Pfützer RH, et al. (2000) SPINK1/PSTI polymorphisms act as disease modifiers in fa- milial and idiopathic chronic pancreatitis. Gastroenterology 119(3):615-623.
  25. Keim V (2008) Role of genetic disorders in acute recurrent pancreatitis. World J Gastroenterol 14(7):1011-1015.
  26. Hodgson JG, et al. (1999) A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23(1):181-192.
  27. Gray M, et al. (2008) Full-length human mutant huntingtin with a stable polyglut- amine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28(24):6182-6195.
  28. Zheng S, et al. (2010) Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLoS Genet 6(2):e1000838.
  29. Neveklovska M, Clabough EB, Steffan JS, Zeitlin SO (2012) Deletion of the huntingtin proline-rich region does not significantly affect normal huntingtin function in mice. J Huntingtons Dis 1(1):71-87.
  30. Wexler NS, et al. (1987) Homozygotes for Huntington's disease. Nature 326(6109): 194-197.
  31. Myers RH, et al. (1989) Homozygote for Huntington disease. Am J Hum Genet 45(4): 615-618.
  32. Godin JD, et al. (2010) Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron 67(3):392-406.
  33. Tong Y, et al. (2011) Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development. J Neurosci 31(41):14794-14799.
  34. Haremaki T, Deglincerti A, Brivanlou AH (2015) Huntingtin is required for ciliogenesis and neurogenesis during early Xenopus development. Dev Biol 408(2):305-315.
  35. Delacour A, Nepote V, Trumpp A, Herrera PL (2004) Nestin expression in pancreatic exocrine cell lineages. Mech Dev 121(1):3-14.
  36. Graf R, Bimmler D (2006) Biochemistry and biology of SPINK-PSTI and monitor pep- tide. Endocrinol Metab Clin North Am 35(2):333-343, ix.
  37. Chen JM, Mercier B, Audrezet MP, Ferec C (2000) Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis. J Med Genet 37(1):67-69.
  38. Liddle RA (2006) Pathophysiology of SPINK mutations in pancreatic development and disease. Endocrinol Metab Clin North Am 35(2):345-356, x.
  39. O'Reilly DA, et al. (2008) The SPINK1 N34S variant is associated with acute pancrea- titis. Eur J Gastroenterol Hepatol 20(8):726-731.
  40. Tukiainen E, et al. (2005) Pancreatic secretory trypsin inhibitor (SPINK1) gene muta- tions in patients with acute pancreatitis. Pancreas 30(3):239-242.
  41. Wang J, et al. (2008) Expression pattern of serine protease inhibitor kazal type 3 (Spink3) during mouse embryonic development. Histochem Cell Biol 130(2):387-397.
  42. Ohmuraya M, et al. (2005) Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice. Gastroenterology 129(2):696-705.
  43. Romac JM, et al. (2010) Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. Am J Physiol Gastrointest Liver Physiol 298(4):G518-G524.
  44. Li SH, Li XJ (2004) Huntingtin and its role in neuronal degeneration. Neuroscientist 10(5):467-475.
  45. Drouet V, et al. (2009) Sustained effects of nonallele-specific Huntingtin silencing. Ann Neurol 65(3):276-285.
  46. Bhat KP, Yan S, Wang CE, Li S, Li XJ (2014) Differential ubiquitination and degrada- tion of huntingtin fragments modulated by ubiquitin-protein ligase E3A. Proc Natl Acad Sci USA 111(15):5706-5711.
  47. Gout J, et al. (2013) Isolation and culture of mouse primary pancreatic acinar cells. J Vis Exp, 10.3791/50514. · DOI
  48. Halangk W, et al. (2000) Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest 106(6):773-781.

Cited by

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Authors
Wang, G., Liu, X., Gaertig, M. A., Li, S., & Li, X.-J.
Affiliations
Emory University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2016-03-07
Volume
113
Issue
12
Pages
3359-3364
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1524575113
PMC
PMC4812735
OpenAlex
W2295033318
Cited by
146
References
1
Citations by year
2026: 7 · 2025: 13 · 2024: 12 · 2023: 9 · 2022: 18 · 2021: 12 · 2020: 14 · 2019: 25 · 2018: 14 · 2017: 18 · 2016: 4
FWCI
11.44
Type
journal article
Language
en
Open access
Licence
www.pnas.org/preview_site/misc/userlicense.xhtml (vor, 184 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Institute on Aging (AG019206)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS041669, NS095279)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
huntingtin, Huntington's disease, acute pancreatitis, pancreatic acinar cells, trypsin inhibitor, neurodegeneration
MeSH terms
Huntingtin Protein, Acute Disease, Animals, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Pancreatitis, Mice, Knockout, Mice

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