Post-translational modifications of α-synuclein contribute to neurodegeneration in the colon of elderly individuals

Xuan,Qi; Zhang,Yu‑Xian; Liu,Dian‑Gang; Chan,Piu; Xu,Sheng‑Li; Cui,Ye‑Qing

doi:10.3892/mmr.2016.5166

Post-translational modifications of α-synuclein contribute to neurodegeneration in the colon of elderly individuals

Authors:
- Qi Xuan
- Yu‑Xian Zhang
- Dian‑Gang Liu
- Piu Chan
- Sheng‑Li Xu
- Ye‑Qing Cui
View Affiliations

Affiliations: Department of Nutrition, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China, Department of Internal Medicine, Beijing Moslem Hospital, Beijing 100054, P.R. China, Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China, Department of Neurobiology, Institute of Geriatrics of Beijing, Xuanwu Hospital, Capital Medical University, Key Laboratory for Neurodegenerative Disease of Ministry of Education, Beijing 100053, P.R. China
Published online on: April 22, 2016 https://doi.org/10.3892/mmr.2016.5166
Pages: 5077-5083
Copyright: © Xuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Synucleinopathies and abnormalities in the nerves of the enteric nervous system are hypothesized to be involved in age-associated motility disorders. The aim of the present study was to investigate the expression of various antigens, including α‑synuclein (Syn) and its post‑translational modified forms, in the human colon at various ages. In addition, the study aimed to correlate the expression of Syn with neurodegeneration. Immunohistochemistry was used to detect the expression of neurofilament (NF), Syn, as well as its nitrated (N) form in the healthy colonic tissue of 12 young (34.08±5.12 years), 10 middle‑aged (51.80±3.52 years), and 11 elderly (75.82±7.70 years) individuals. To the best of our knowledge, the current study is the first to demonstrate the presence of N‑Syn in the colonic tissue. N‑Syn was identified in the upper layer of the mucosa and submucosa layer. Furthermore, Syn (wild‑type) was present in the mucosa and submucosa. The number of NF‑positive neurons in the submucosal layer declined significantly with age (P<0.01). In addition, Syn and N‑Syn significantly increased during aging (P<0.01). Furthermore, a negative correlation was identified between neuron number and synucleinopathies, indicating the abnormal accumulation of both wild-type Syn and N‑Syn in the mucosa, submucosa, muscle layer and myenteric plexus. The present study demonstrates that the Syn pathology may be linked to colic neuronal degeneration during normal aging, and this link may cause functional deficits.

View Figures

View References

1	Norton C: Constipation in older patients: Effects on quality of life. Br J Nurs. 15:188–192. 2006. View Article : Google Scholar : PubMed/NCBI
2	Wattchow D, Brookes S, Murphy E, Carbone S, De Fontgalland D and Costa M: Regional variation in the neurochemical coding of the myenteric plexus of the human colon and changes in patients with slow transit constipation. Neurogastroenterol Motil. 20:1298–1305. 2008. View Article : Google Scholar : PubMed/NCBI
3	Phillips RJ, Pairitz JC and Powley TL: Age-related neuronal loss in the submucosal plexus of the colon of Fischer 344 rats. Neurobiol Aging. 28:1124–1137. 2007. View Article : Google Scholar
4	Phillips RJ and Powley TL: Innervation of the gastrointestinal tract: Patterns of aging. Auton Neurosci. 136:1–19. 2007. View Article : Google Scholar : PubMed/NCBI
5	Bellani S, Sousa VL, Ronzitti G, Valtorta F, Meldolesi J and Chieregatti E: The regulation of synaptic function by alpha-synuclein. Commun Integr Biol. 3:106–109. 2010. View Article : Google Scholar : PubMed/NCBI
6	Sousa VL, Bellani S, Giannandrea M, Yousuf M, Valtorta F, Meldolesi J and Chieregatti E: {alpha}-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics. Mol Biol Cell. 20:3725–3739. 2009. View Article : Google Scholar : PubMed/NCBI
7	Adamczyk A, Solecka J and Strosznajder JB: Expression of alpha-synuclein in different brain parts of adult and aged rats. J Physiol Pharmacol. 56:29–37. 2005.PubMed/NCBI
8	Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White lii C, Akiyama H, Caviness JN, Shill HA, Sabbagh MN and Walker DG: Arizona Parkinson's Disease Consortium: Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 119:689–702. 2010. View Article : Google Scholar : PubMed/NCBI
9	Wenning GK and Jellinger KA: The role of alpha-synuclein and tau in neurodegenerative movement disorders. Curr Opin Neurol. 18:357–362. 2005. View Article : Google Scholar : PubMed/NCBI
10	Phillips RJ, Walter GC, Wilder SL, Baronowsky EA and Powley TL: Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: Autonomic pathway implicated in Parkinson's disease? Neuroscience. 153:733–750. 2008. View Article : Google Scholar : PubMed/NCBI
11	Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg M, Shen J, Takio K and Iwatsubo T: Alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 4:160–164. 2002.PubMed/NCBI
12	Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ and Lee VM: Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 290:985–989. 2000. View Article : Google Scholar : PubMed/NCBI
13	Chen LI and Feany MB: Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a drosophila model of parkinson disease. Nat Neurosci. 8:657–663. 2005. View Article : Google Scholar : PubMed/NCBI
14	Yamin G, Uversky VN and Fink AL: Nitration inhibits fibrillation of human alpha-synuclein in vitro by formation of soluble oligomers. FEBS Lett. 542:147–152. 2003. View Article : Google Scholar : PubMed/NCBI
15	Yu Z, Xu X, Xiang Z, Zhou J, Zhang Z, Hu C and He C: Nitrated alpha-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats. PLoS One. 5:e99562010. View Article : Google Scholar : PubMed/NCBI
16	Xuan Q, Xu SL, Lu DH, Yu S, Zhou M, Uéda K, Cui YQ, Zhang BY and Chan P: Increased expression of α-synuclein in aged human brain associated with neuromelanin accumulation. J Neural Transm (Vienna). 118:1575–1583. 2011. View Article : Google Scholar
17	Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, et al: Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience. 145:539–555. 2007. View Article : Google Scholar : PubMed/NCBI
18	Madsen JL and Graff J: Effects of ageing on gastrointestinal motor function. Age Ageing. 33:154–159. 2004. View Article : Google Scholar : PubMed/NCBI
19	McHugh SM and Diamant NE: Effect of age, gender and parity on anal canal pressures. Contribution of impaired anal sphincter function to fecal incontinence. Dig Dis Sci. 32:726–736. 1987. View Article : Google Scholar : PubMed/NCBI
20	Phillips RJ, Kieffer EJ and Powley TL: Aging of the myenteric plexus: Neuronal loss is specific to cholinergic neurons. Auton Neurosci. 106:69–83. 2003. View Article : Google Scholar : PubMed/NCBI
21	Wade PR: Aging and neural control of the GI tractI. Age-related changes in the enteric nervous system. Am J Physiol Gastrointest Liver Physiol. 283:G489–G495. 2002. View Article : Google Scholar : PubMed/NCBI
22	Bernard CE, Gibbons SJ, Gomez Pinilla PJ, Lurken MS, Schmalz PF, Roeder JL, Linden D, Cima RR, Dozois EJ, Larson DW, et al: Effect of age on the enteric nervous system of the human colon. Neurogastroenterol Motil. 21:7462009. View Article : Google Scholar : PubMed/NCBI
23	Lebouvier T, Chaumette T, Damier P, Coron E, Touchefeu Y, Vrignaud S, Naveilhan P, Galmiche JP, Bruley des Varannes S, Derkinderen P and Neunlist M: Pathological lesions in colonic biopsies during Parkinson's disease. Gut. 57:1741–1743. 2008. View Article : Google Scholar : PubMed/NCBI
24	Phillips RJ, Walter GC, Ringer BE, Higgs KM and Powley TL: Alpha-synuclein immunopositive aggregates in the myenteric plexus of the aging Fischer 344 rat. Exp Neurol. 220:109–119. 2009. View Article : Google Scholar : PubMed/NCBI
25	Lebouvier T, Neunlist M, Burley des Varannes S, Coron E, Drouard A, N'Guyen JM, Chaumette T, Tasselli M, Paillusson S, Flamand M, et al: Colonic biopsies to assess the neuropathology of parkinson's disease and its relationship with symptoms. PLoS One. 5:e127282010. View Article : Google Scholar : PubMed/NCBI
26	Choi DY, Zhang J and Bing G: Aging enhances the neuroinflammatory response and alpha-synuclein nitration in rats. Neurobiol Aging. 31:1649–1653. 2010. View Article : Google Scholar
27	Siebert H, Kahle PJ, Kramer ML, Isik T, Schlüter OM, Schulz-Schaeffer WJ and Brück W: Over-expression of alpha-synuclein in the nervous system enhances axonal degeneration after peripheral nerve lesion in a transgenic mouse strain. J Neurochem. 114:1007–1018. 2010.PubMed/NCBI
28	Orimo S, Uchihara T, Nakamura A, Mori F, Kakita A, Wakabayashi K and Takahashi H: Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in parkinson's disease. Brain. 131:642–650. 2008. View Article : Google Scholar
29	Wattchow D, Brookes S, Murphy E, Carbone S, De Fontgalland D and Costa M: Regional variation in the neurochemical coding of the myenteric plexus of the human colon and changes in patients with slow transit constipation. Neurogastroenterol Motil. 20:1298–1305. 2008. View Article : Google Scholar : PubMed/NCBI
30	Migliore L and Coppedè F: Environmental-induced oxidative stress in neurodegenerative disorders and aging. Mutat Res. 674:73–84. 2009. View Article : Google Scholar
31	Miwa H, Kubo T, Suzuki A and Kondo T: Intragastric proteasome inhibition induces alpha-synuclein-immunopositive aggregations in neurons in the dorsal motor nucleus of the vagus in rats. Neurosci Lett. 401:146–149. 2006. View Article : Google Scholar : PubMed/NCBI
32	Takahashi M, Ko LW, Kulathingal J, Jiang P, Sevlever D and Yen SH: Oxidative stress-induced phosphorylation, degradation and aggregation of alpha-synuclein are linked to upregulated CK2 and cathepsin D. Eur J Neurosci. 26:863–874. 2007. View Article : Google Scholar : PubMed/NCBI
33	McCormack AL, Mak SK, Shenasa M, Langston WJ, Forno LS and Di Monte DA: Pathological modifications of alpha-synuclein in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated squirrel monkeys. J Neuropath Exp Neur. 67:793–802. 2008. View Article : Google Scholar
34	Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ and Lee VM: Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci. 28:7687–7698. 2008. View Article : Google Scholar : PubMed/NCBI
35	Hodara R, Norris EH, Giasson BI, Mishizen-Eberz AJ, Lynch DR, Lee VM and Ischiropoulos H: Functional consequences of alpha-synuclein tyrosine nitration: Diminished binding to lipid vesicles and increased fibril formation. J Biol Chem. 279:47746–47753. 2004. View Article : Google Scholar : PubMed/NCBI
36	Devi L, Raghavendran V, Prabhu BM, Avadhani NG and Anandatheerthavarada HK: Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem. 283:9089–9100. 2008. View Article : Google Scholar : PubMed/NCBI
37	Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, Wong J, Takenouchi T, Hashimoto M and Masliah E: Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 157:401–410. 2000. View Article : Google Scholar : PubMed/NCBI
38	Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E and Lee SJ: Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA. 106:13010–13015. 2009. View Article : Google Scholar : PubMed/NCBI