The bowel and beyond: the enteric nervous system in neurological disorders (original) (raw)

• Gershon, M. D. The Second Brain (Harper Collins, 1998).
  Google Scholar
• Furness, J. B., Callaghan, B. P., Rivera, L. R. & Cho, H. J. The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv. Exp. Med. Biol. 817, 39–71 (2014).
  PubMed Google Scholar
• Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell 154, 274–284 (2013).
  CAS PubMed Google Scholar
• Turner, J. R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).
  CAS PubMed Google Scholar
• Mowat, A. M. & Agace, W. W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14, 667–685 (2014).
  CAS PubMed Google Scholar
• Langley, J. N. The Autonomic Nervous System, Part 1 [1921] (Cornell Univ. Library, 2010).
  Google Scholar
• Furness, J. B. The Enteric Nervous System (Blackwell Publishing, 2006).
  Google Scholar
• Gershon, M. D. Developmental determinants of the independence and complexity of the enteric nervous system. Trends Neurosciences 33, 446–456 (2010).
  CAS Google Scholar
• Forsythe, P., Bienenstock, J. & Kunze, W. A. Vagal pathways for microbiome–brain–gut axis communication. Adv. Exp. Med. Biol. 817, 115–133 (2014).
  PubMed Google Scholar
• Rush, A. J. et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol. Psychiatry 47, 276–286 (2000).
  CAS PubMed Google Scholar
• George, M. S. et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol. Psychiatry 47, 287–295 (2000).
  CAS PubMed Google Scholar
• Sampson, T. R. & Mazmanian, S. K. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 17, 565–576 (2015).
  CAS PubMed PubMed Central Google Scholar
• Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).
  CAS PubMed PubMed Central Google Scholar
• Mayer, E. A., Knight, R., Mazmanian, S. K., Cryan, J. F. & Tillisch, K. Gut microbes and the brain: paradigm shift in neuroscience. J. Neurosci. 34, 15490–15496 (2014).
  PubMed PubMed Central Google Scholar
• Tam, P. K. Hirschsprung's disease: a bridge for science and surgery. J. Pediatr. Surg. 51, 18–22 (2016).
  PubMed Google Scholar
• Heuckeroth, R. O. Hirschsprung's disease, Down syndrome, and missing heritability: too much collagen slows migration. J. Clin. Invest. 125, 4323–4326 (2015).
  PubMed PubMed Central Google Scholar
• Amiel, J. & Lyonnet, S. Hirschsprung disease, associated syndromes, and genetics: a review. J. Med. Genet. 38, 729–739 (2001).
  CAS PubMed PubMed Central Google Scholar
• Bern, C. Chagas' disease. N. Engl. J. Med. 373, 1882 (2015).
  PubMed Google Scholar
• Avetisyan, M., Schill, E. M. & Heuckeroth, R. O. Building a second brain in the bowel. J. Clin. Invest. 125, 899–907 (2015).
  PubMed PubMed Central Google Scholar
• Klingelhoefer, L. & Reichmann, H. Pathogenesis of Parkinson disease — the gut–brain axis and environmental factors. Nat. Rev. Neurol. 11, 625–636 (2015).
  CAS PubMed Google Scholar
• Collins, S. J., Lawson, V. A. & Masters, C. L. Transmissible spongiform encephalopathies. Lancet 363, 51–61 (2004).
  CAS PubMed Google Scholar
• Prusiner, S. B. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601–623 (2013).
  CAS PubMed PubMed Central Google Scholar
• Aguzzi, A. Unraveling prion strains with cell biology and organic chemistry. Proc. Natl Acad. Sci. USA 105, 11–12 (2008).
  CAS PubMed Google Scholar
• Cronier, S. et al. Endogenous prion protein conversion is required for prion-induced neuritic alterations and neuronal death. FASEB J. 26, 3854–3861 (2012).
  CAS PubMed Google Scholar
• Ghosh, S. Mechanism of intestinal entry of infectious prion protein in the pathogenesis of variant Creutzfeldt–Jakob disease. Adv. Drug Deliv. Rev. 56, 915–920 (2004).
  CAS PubMed Google Scholar
• Kujala, P. et al. Prion uptake in the gut: identification of the first uptake and replication sites. PLoS Pathog. 7, e1002449 (2011).
  CAS PubMed PubMed Central Google Scholar
• Chiocchetti, R. et al. Anatomical evidence for ileal Peyer's patches innervation by enteric nervous system: a potential route for prion neuroinvasion? Cell Tissue Res. 332, 185–194 (2008).
  PubMed Google Scholar
• Albanese, V. et al. Evidence for prion protein expression in enteroglial cells of the myenteric plexus of mouse intestine. Auton. Neurosci. 140, 17–23 (2008).
  CAS PubMed Google Scholar
• Martin, G. R. et al. Endogenous cellular prion protein regulates contractility of the mouse ileum. Neurogastroenterol. Motil. 24, e412–424 (2012).
  CAS PubMed Google Scholar
• Posar, A., Resca, F. & Visconti, P. Autism according to diagnostic and statistical manual of mental disorders 5th edition: the need for further improvements. J. Pediatr. Neurosci. 10, 146–148 (2015).
  PubMed PubMed Central Google Scholar
• McElhanon, B. O., McCracken, C., Karpen, S. & Sharp, W. G. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics 133, 872–883 (2014).
  PubMed Google Scholar
• Halfon, N. & Kuo, A. A. What DSM-5 could mean to children with autism and their families. JAMA Pediatr. 167, 608–613 (2013).
  PubMed Google Scholar
• Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011).
  CAS PubMed Google Scholar
• Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).
  CAS PubMed PubMed Central Google Scholar
• Neale, B. M. et al. Patterns and rates of exonic De novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).
  CAS PubMed PubMed Central Google Scholar
• O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of De novo mutations. Nature 485, 246–250 (2012).
  CAS PubMed PubMed Central Google Scholar
• O'Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).
  CAS PubMed PubMed Central Google Scholar
• Schulze, T. G. & McMahon, F. J. Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping. Hum. Hered. 58, 131–138 (2004).
  PubMed Google Scholar
• Bernier, R. et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158, 263–276 (2014).
  CAS PubMed PubMed Central Google Scholar
• Sweatt, J. D. Pitt–Hopkins syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp. Mol. Med. 45, e21 (2013).
  PubMed PubMed Central Google Scholar
• Grubisic, V., Kennedy, A. J., Sweatt, J. D. & Parpura, V. Pitt–Hopkins mouse model has altered particular gastrointestinal transits in vivo. Autism Res. 8, 629–633 (2015).
  PubMed PubMed Central Google Scholar
• Marler, S. et al. Brief report: whole blood serotonin levels and gastrointestinal symptoms in autism spectrum disorder. J. Autism Dev. Disord. 46, 1124–1130 (2016).
  PubMed PubMed Central Google Scholar
• Matondo, R. B. et al. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G963–G968 (2009).
  CAS PubMed Google Scholar
• Morrissey, J. J., Walker, M. N. & Lovenberg, W. The absence of tryptophan hydroxylase activity in blood platelets. Proc. Soc. Exp. Biol. Med. 154, 496–499 (1977).
  CAS PubMed Google Scholar
• Lesch, K. P., Wolozin, B. L., Murphy, D. L. & Riederer, P. Primary structure of the human platelet serotonin (5-HT) uptake site: identity with the brain 5-HT transporter. J. Neurochem. 60, 2319–2322 (1993).
  CAS PubMed Google Scholar
• Veenstra-VanderWeele, J. et al. Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proc. Natl Acad. Sci. USA 109, 5469–5474 (2012).
  CAS PubMed Google Scholar
• Margolis, K. G. et al. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J. Clin. Invest. 126, 2221–2235 (2016).
  PubMed PubMed Central Google Scholar
• Bromley, R. L. et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J. Neurol. Neurosurg. Psychiatry 84, 637–643 (2013).
  PubMed PubMed Central Google Scholar
• Christensen, J. et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309, 1696–1703 (2013).
  CAS PubMed PubMed Central Google Scholar
• Roullet, F. I., Lai, J. K. & Foster, J. A. In utero exposure to valproic acid and autism — a current review of clinical and animal studies. Neurotoxicol. Teratol. 36, 47–56 (2013).
  CAS PubMed Google Scholar
• de Theije, C. G. et al. Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav. Immun. 37, 240–247 (2014).
  CAS PubMed Google Scholar
• Ghia, J. E. et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology 137, 1649–1660 (2009).
  CAS PubMed Google Scholar
• Haub, S. et al. Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter. Neurogastroenterol. Motil. 22, 826–e229 (2010).
  CAS PubMed PubMed Central Google Scholar
• Bischoff, S. C. et al. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am. J. Physiol. Gastrointest Liver Physiol. 296, G685–G695 (2009).
  CAS PubMed Google Scholar
• Gershon, M. D. Serotonin is a sword and a shield of the bowel: serotonin plays offense and defense. Trans. Am. Clin. Climatol. Assoc. 123, 268–280; discussion 280 (2012).
  PubMed PubMed Central Google Scholar
• Gershon, M. D. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 20, 14–21 (2013).
  CAS PubMed PubMed Central Google Scholar
• Liu, Z., Li, N. & Neu, J. Tight junctions, leaky intestines, and pediatric diseases. Acta Paediatr. 94, 386–393 (2005).
  CAS PubMed Google Scholar
• D'Eufemia, P. et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 85, 1076–1079 (1996).
  CAS PubMed Google Scholar
• Robertson, M. A. et al. Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study. J. Autism Dev. Disord. 38, 1066–1071 (2008).
  PubMed Google Scholar
• de Magistris, L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J. Pediatr. Gastroenterol. Nutr. 51, 418–424 (2010).
  PubMed Google Scholar
• Malkova, N. V., Yu, C. Z., Hsiao, E. Y., Moore, M. J. & Patterson, P. H. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun. 26, 607–616 (2012).
  CAS PubMed PubMed Central Google Scholar
• Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).
  CAS PubMed PubMed Central Google Scholar
• Neunlist, M. et al. The digestive neuronal–glial–epithelial unit: a new actor in gut health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 90–100 (2013).
  CAS PubMed Google Scholar
• Jankovic, J. Parkinson's disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79, 368–376 (2008).
  CAS PubMed Google Scholar
• Qualman, S. J., Haupt, H. M., Yang, P. & Hamilton, S. R. Esophageal Lewy bodies associated with ganglion cell loss in achalasia. Similarity to Parkinson's disease. Gastroenterology 87, 848–856 (1984).
  CAS PubMed Google Scholar
• Kupsky, W. J., Grimes, M. M., Sweeting, J., Bertsch, R. & Cote, L. J. Parkinson's disease and megacolon: concentric hyaline inclusions (Lewy bodies) in enteric ganglion cells. Neurology 37, 1253–1255 (1987).
  CAS PubMed Google Scholar
• Wakabayashi, K., Takahashi, H., Takeda, S., Ohama, E. & Ikuta, F. Parkinson's disease: the presence of Lewy bodies in Auerbach's and Meissner's plexuses. Acta Neuropathol. (Berl.) 76, 217–221 (1988).
  CAS Google Scholar
• Wakabayashi, K., Takahashi, H., Ohama, E. & Ikuta, F. Tyrosine hydroxylase-immunoreactive intrinsic neurons in the Auerbach's and Meissner's plexuses of humans. Neurosci. Lett. 96, 259–263 (1989).
  CAS PubMed Google Scholar
• Li, Z. S., Pham, T. D., Tamir, H., Chen, J. J. & Gershon, M. D. Enteric dopaminergic neurons: definition, developmental lineage, and effects of extrinsic denervation. J. Neurosci. 24, 1330–1339 (2004).
  CAS PubMed PubMed Central Google Scholar
• Li, Z. S., Schmauss, C., Cuenca, A., Ratcliffe, E. & Gershon, M. D. Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wild-type and knock-out mice. J. Neurosci. 26, 2798–2807 (2006).
  CAS PubMed PubMed Central Google Scholar
• Tieu, K. A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb. Perspect. Med. 1, a009316 (2011).
  PubMed PubMed Central Google Scholar
• Anderson, G. et al. Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease. Exp. Neurol. 207, 4–12 (2007).
  CAS PubMed PubMed Central Google Scholar
• Chandra, S., Gallardo, G., Fernandez-Chacon, R., Schluter, O. M. & Sudhof, T. C. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123, 383–396 (2005).
  CAS PubMed Google Scholar
• Westphal, C. H. & Chandra, S. S. Monomeric synucleins generate membrane curvature. J. Biol. Chem. 288, 1829–1840 (2013).
  CAS PubMed Google Scholar
• Vargas, K. J. et al. Synucleins regulate the kinetics of synaptic vesicle endocytosis. J. Neurosci. 34, 9364–9376 (2014).
  PubMed PubMed Central Google Scholar
• Braak, H. & Braak, E. Pathoanatomy of Parkinson's disease. J. Neurol. 247 (Suppl. 2), II/3–II/10 (2000).
  Google Scholar
• Preterre, C. et al. Optimizing Western Blots for the detection of endogenous α-synuclein in the enteric nervous system. J. Parkinsons Dis. 5, 765–772 (2015).
  CAS PubMed Google Scholar
• Aldecoa, I. et al. Alpha-synuclein immunoreactivity patterns in the enteric nervous system. Neurosci. Lett. 602, 145–149 (2015).
  CAS PubMed Google Scholar
• Miraglia, F., Betti, L., Palego, L. & Giannaccini, G. Parkinson's disease and alpha-synucleinopathies: from arising pathways to therapeutic challenge. Cent. Nerv. Syst. Agents Med. Chem. 15, 109–116 (2015).
  CAS PubMed Google Scholar
• Hallett, P. J., McLean, J. R., Kartunen, A., Langston, J. W. & Isacson, O. Alpha-synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. Neurobiol. Dis. 47, 258–267 (2012).
  CAS PubMed PubMed Central Google Scholar
• Wang, L., Fleming, S. M., Chesselet, M. F. & Tache, Y. Abnormal colonic motility in mice overexpressing human wild-type α-synuclein. Neuroreport 19, 873–876 (2008).
  CAS PubMed PubMed Central Google Scholar
• Wang, L. et al. Mice overexpressing wild-type human α-synuclein display alterations in colonic myenteric ganglia and defecation. Neurogastroenterol. Motil. 24, e425–e436 (2012).
  CAS PubMed PubMed Central Google Scholar
• Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).
  CAS PubMed Google Scholar
• Kruger, R. et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18, 106–108 (1998).
  CAS PubMed Google Scholar
• Kuo, Y. M. et al. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes. Hum. Mol. Genet. 19, 1633–1650 (2010).
  CAS PubMed PubMed Central Google Scholar
• Lebouvier, T. et al. Routine colonic biopsies as a new tool to study the enteric nervous system in living patients. Neurogastroenterol. Motil. 22, e11–e14 (2010).
  CAS PubMed Google Scholar
• Gold, A., Turkalp, Z. T. & Munoz, D. G. Enteric alpha-synuclein expression is increased in Parkinson's disease but not Alzheimer's disease. Mov. Disord. 28, 237–240 (2013).
  CAS PubMed Google Scholar
• US Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. JAMA 315, 2564-2575 (2016).
• Hilton, D. et al. Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease. Acta Neuropathol. 127, 235–241 (2014).
  CAS PubMed Google Scholar
• Shannon, K. M. et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease. Mov. Disord. 27, 709–715 (2012).
  PubMed Google Scholar
• Visanji, N. P. et al. Colonic mucosal α-synuclein lacks specificity as a biomarker for Parkinson disease. Neurology 84, 609–616 (2015).
  CAS PubMed PubMed Central Google Scholar
• Stokholm, M. G., Danielsen, E. H., Hamilton-Dutoit, S. J. & Borghammer, P. Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann. Neurol. 79, 940–949 (2016).
  CAS PubMed Google Scholar
• Singaram, C. et al. Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation. Lancet 346, 861–864 (1995).
  CAS PubMed Google Scholar
• Annerino, D. M. et al. Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol. 124, 665–680 (2012).
  PubMed PubMed Central Google Scholar
• Pickel, V. M., Beckley, S. C., Joh, T. H. & Reis, D. J. Ultrastructural immunocytochemical localization of tyrosine hydroxylase in the neostriatum. Brain Res. 225, 373–385 (1981).
  CAS PubMed Google Scholar
• Weiner, N. Regulation of norepinephrine biosynthesis. Annu. Rev. Pharmacol. 10, 273–290 (1970).
  CAS PubMed Google Scholar
• Braak, E. et al. alpha-synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei. Acta Neuropathol. 101, 195–201 (2001).
  CAS PubMed Google Scholar
• Del Tredici, K., Rub, U., De Vos, R. A., Bohl, J. R. & Braak, H. Where does parkinson disease pathology begin in the brain? J. Neuropathol. Exp. Neurol. 61, 413–426 (2002).
  PubMed Google Scholar
• Braak, H., Rub, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural Transm. 110, 517–536 (2003).
  CAS PubMed Google Scholar
• Del Tredici, K. & Duda, J. E. Peripheral Lewy body pathology in Parkinson's disease and incidental Lewy body disease: four cases. J. Neurol. Sci. 310, 100–106 (2011).
  PubMed Google Scholar
• Phillips, R. J., Walter, G. C., Wilder, S. L., Baronowsky, E. A. & Powley, T. L. Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: autonomic pathway implicated in Parkinson's disease? Neuroscience 153, 733–750 (2008).
  CAS PubMed PubMed Central Google Scholar
• Gorell, J. M., Johnson, C. C., Rybicki, B. A., Peterson, E. L. & Richardson, R. J. The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology 50, 1346–1350 (1998).
  CAS PubMed Google Scholar
• Pan-Montojo, F. et al. Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS ONE 5, e8762 (2010).
  PubMed PubMed Central Google Scholar
• Pan-Montojo, F. et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci. Rep. 2, 898 (2012).
  PubMed PubMed Central Google Scholar
• Ulusoy, A. et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol. Med. 5, 1051–1059 (2013).
  CAS PubMed Central Google Scholar
• Holmqvist, S. et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805–820 (2014).
  PubMed Google Scholar
• Svensson, E. et al. Vagotomy and subsequent risk of Parkinson's disease. Ann. Neurol. 78, 522–529 (2015).
  PubMed Google Scholar
• Tysnes, O. B. et al. Does vagotomy reduce the risk of Parkinson's disease? Ann. Neurol. 78, 1011–1012 (2015).
  PubMed Google Scholar
• Jellinger, K. A. A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders. Biochim. Biophys. Acta 1792, 730–740 (2009).
  CAS PubMed Google Scholar
• Kalaitzakis, M. E., Graeber, M. B., Gentleman, S. M. & Pearce, R. K. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of α-synuclein staging. Neuropathol. Appl. Neurobiol. 34, 284–295 (2008).
  CAS PubMed Google Scholar
• Kingsbury, A. E. et al. Brain stem pathology in Parkinson's disease: an evaluation of the Braak staging model. Mov. Disord. 25, 2508–2515 (2010).
  PubMed Google Scholar
• Ubhi, K. & Masliah, E. Alzheimer's disease: recent advances and future perspectives. J. Alzheimers Dis. 33, S185–S194 (2013).
  PubMed Google Scholar
• Schliebs, R. Basal forebrain cholinergic dysfunction in Alzheimer's disease — interrelationship with beta-amyloid, inflammation and neurotrophin signaling. Neurochem. Res. 30, 895–908 (2005).
  CAS PubMed Google Scholar
• Arai, H. et al. Expression patterns of beta-amyloid precursor protein (β-APP) in neural and nonneural human tissues from Alzheimer's disease and control subjects. Ann. Neurol. 30, 686–693 (1991).
  CAS PubMed Google Scholar
• Puig, K. L., Swigost, A. J., Zhou, X., Sens, M. A. & Combs, C. K. Amyloid precursor protein expression modulates intestine immune phenotype. J. Neuroimmune Pharmacol. 7, 215–230 (2012).
  PubMed Google Scholar
• Semar, S. et al. Changes of the enteric nervous system in amyloid-β protein precursor transgenic mice correlate with disease progression. J. Alzheimers Dis. 36, 7–20 (2013).
  CAS PubMed Google Scholar
• Puig, K. L. et al. Overexpression of mutant amyloid-β protein precursor and presenilin 1 modulates enteric nervous system. J. Alzheimers Dis. 44, 1263–1278 (2015).
  CAS PubMed PubMed Central Google Scholar
• Joachim, C. L., Mori, H. & Selkoe, D. J. Amyloid β-protein deposition in tissues other than brain in Alzheimer's disease. Nature 341, 226–230 (1989).
  CAS PubMed Google Scholar
• Deguchi, E., Iwai, N., Goto, Y., Yanagihara, J. & Fushiki, S. An immunohistochemical study of neurofilament and microtubule-associated Tau protein in the enteric innervation in Hirschsprung's disease. J. Pediatr. Surg. 28, 886–890 (1993).
  CAS PubMed Google Scholar
• Tam, P. K. & Owen, G. An immunohistochemical study of neuronal microtubule-associated proteins in Hirschsprung's disease. Hum. Pathol. 24, 424–431 (1993).
  CAS PubMed Google Scholar
• Phillips, R. J., Walter, G. C., Ringer, B. E., Higgs, K. M. & Powley, T. L. Alpha-synuclein immunopositive aggregates in the myenteric plexus of the aging Fischer 344 rat. Exp. Neurol. 220, 109–119 (2009).
  CAS PubMed PubMed Central Google Scholar
• Shankle, W. R. et al. Studies of the enteric nervous system in Alzheimer disease and other dementias of the elderly: enteric neurons in Alzheimer disease. Mod. Pathol. 6, 10–14 (1993).
  CAS PubMed Google Scholar
• Jovicic, A., Paul, J. W. 3rd & Gitler, A. D. Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia. J. Neurochem. http://dx.doi.org/10.1111/jnc.13642 (2016).
• Geser, F., Martinez-Lage, M., Kwong, L. K., Lee, V. M. & Trojanowski, J. Q. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J. Neurol. 256, 1205–1214 (2009).
  PubMed PubMed Central Google Scholar
• Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 (2008).
  CAS PubMed Google Scholar
• Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).
  CAS PubMed Google Scholar
• Chio, A. et al. Extensive genetics of ALS: a population-based study in Italy. Neurology 79, 1983–1989 (2012).
  PubMed PubMed Central Google Scholar
• Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
  CAS PubMed Google Scholar
• Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M. & Baloh, R. H. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 106, 18809–18814 (2009).
  CAS PubMed Google Scholar
• Guo, Y. et al. HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 1460, 88–95 (2012).
  CAS PubMed Google Scholar
• Esmaeili, M. A., Panahi, M., Yadav, S., Hennings, L. & Kiaei, M. Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis. Int. J. Exp. Pathol. 94, 56–64 (2013).
  CAS PubMed PubMed Central Google Scholar
• Herdewyn, S. et al. Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T) mice. Mol. Neurodegener. 9, 24 (2014).
  PubMed PubMed Central Google Scholar
• Hatzipetros, T. et al. C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 1584, 59–72 (2014).
  CAS PubMed Google Scholar
• Kaur, S. J., McKeown, S. R. & Rashid, S. Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis. Gene 577, 109–118 (2016).
  CAS PubMed Google Scholar
• Wu, S., Yi, J., Zhang, Y. G., Zhou, J. & Sun, J. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol. Rep. 3, e12356 (2015).
  PubMed PubMed Central Google Scholar
• Gross, E. R., Gershon, M. D., Margolis, K. G., Gertsberg, Z. V. & Cowles, R. A. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology 143, 408–417.e2 (2012).
  CAS PubMed PubMed Central Google Scholar
• Natale, G., Pasquali, L., Paparelli, A. & Fornai, F. Parallel manifestations of neuropathologies in the enteric and central nervous systems. Neurogastroenterol. Motil. 23, 1056–1065 (2011).
  CAS PubMed Google Scholar
• Colby, D. W. & Prusiner, S. B. Prions. Cold Spring Harb. Perspect. Biol. 3, a006833 (2011).
  PubMed PubMed Central Google Scholar
• Pinkas, A. & Aschner, M. Advanced glycation end-products and their receptors: related pathologies, recent therapeutic strategies, and a potential model for future neurodegeneration studies. Chem. Res. Toxicol. 29, 707–714 (2016).
  CAS PubMed Google Scholar
• Deng, H., Gao, K. & Jankovic, J. The role of FUS gene variants in neurodegenerative diseases. Nat. Rev. Neurol. 10, 337–348 (2014).
  CAS PubMed Google Scholar
• Sharma, A. et al. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat. Commun. 7, 10465 (2016).
  CAS PubMed PubMed Central Google Scholar
• Parakh, S. & Atkin, J. D. Protein folding alterations in amyotrophic lateral sclerosis. Brain Res. http://dx.doi.org/10.1016/j.brainres.2016.04.010 (2016).
• Gershon, A. A. et al. Varicella zoster virus infection. Nat. Rev. Dis. Primers 1, 15016 (2015).
  PubMed PubMed Central Google Scholar
• Gershon, A. A., Chen, J. & Gershon, M. D. Use of saliva to identify varicella zoster virus infection of the gut. Clin. Infect. Dis. 61, 536–544 (2015).
  CAS PubMed PubMed Central Google Scholar
• Gershon, A. A. et al. Latency of varicella zoster virus in dorsal root, cranial, and enteric ganglia in vaccinated children. Trans. Am. Clin. Climatol. Assoc. 123, 17–33; discussion 33–35 (2012).
  PubMed PubMed Central Google Scholar
• Holland-Cunz, S. et al. Acquired intestinal aganglionosis after a lytic infection with varicella-zoster virus. J. Pediatr. Surg. 41, e29–e31 (2006).
  PubMed Google Scholar
• Levin, M. J. Varicella-zoster virus and virus DNA in the blood and oropharynx of people with latent or active varicella-zoster virus infections. J. Clin. Virol. 61, 487–495 (2014).
  CAS PubMed Google Scholar
• Edelman, D. A. et al. Ogilvie syndrome and herpes zoster: case report and review of the literature. J. Emerg. Med. 39, 696–700 (2009).
  PubMed Google Scholar
• Mehta, S. K. et al. Varicella-zoster virus in the saliva of patients with herpes zoster. J. Infect. Dis. 197, 654–657 (2008).
  PubMed PubMed Central Google Scholar
• Duncan, C. J. & Hambleton, S. Varicella zoster virus immunity: a primer. J. Infect. 71, S47–S53 (2015).
  PubMed Google Scholar
• Johnson, B. H. et al. Annual incidence rates of herpes zoster among an immunocompetent population in the United States. BMC Infect. Dis. 15, 502 (2015).
  PubMed PubMed Central Google Scholar