Alpha-synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system

Noorian, Ali Reza; Rha, Jennifer; Annerino, Dana M.; Bernhard, Douglas; Taylor, Georgia; Greene, James G.

doi:10.1016/j.nbd.2012.06.005

Cited by 74 publications

(51 citation statements)

References 67 publications

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“…Symptomatic effects, such as delayed gastric emptying, as reported in PD patients (39Y41) and other transgenic models (18,42Y44), might occur in our mouse model. Gastrointestinal dysfunction has been reported in detail in other A53T transgenic models, either very apparent (18) or more subtle (42). In addition, a detailed study showed age-related alterations in colonic myenteric ganglia and defecation in a transgenic mouse model that overexpresses wild-type human >-synuclein under the Thy-1 promoter (43,44).…”

Section: Discussionmentioning

confidence: 91%

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

Bencsik

Muselli

Leboidre

et al. 2014

J Neuropathol Exp Neurol

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Alpha-synuclein is a key protein in Parkinson disease (PD) and dementia with Lewy bodies. It is found in Lewy bodies in the brains of PD patients and has been reported in the peripheral nervous system in postmortem tissues from PD patients and in biopsies from patients in the preclinical phase of PD. Here, we used a transgenic mouse model of human synucleinopathies expressing the A53T mutant α-synuclein (TgM83) in which a neurodegenerative process associated with α-synuclein occurs spontaneously and increases with age. In particular, α-synuclein protein phosphorylated at serine 129 (pSer129 α-synuclein) naturally and progressively increases in diseased brains. We examined the time course of pSer129 α-synuclein presence in the gut of these mice between 1.5 and 22 months of age using immunohistochemistry and paraffin-embedded tissue blots. The pSer129 α-synuclein accumulated early (before the onset of motor signs) and persistently in the enteric nervous system and was concomitantly found in the brain. These results suggest that the accumulation of phosphorylated α-synuclein in the enteric and central nervous systems may result from parallel pathologic processes when the disease is linked to a mutation of α-synuclein.

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Section: Discussionmentioning

confidence: 91%

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

Bencsik

Muselli

Leboidre

et al. 2014

J Neuropathol Exp Neurol

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“…For example, transgenic mice overexpressing human wild type α-synuclein had increased α-synuclein immunoreactivity surrounding cholinergic neurons in the colonic myenteric plexus and decreased fecal output at 8–10 months of age [43] and, in a separate study, displayed increased insoluble colonic myenteric α-synuclein and constipation (reduced fecal pellet output and fecal water content) at 12–15 months [44]. In addition, transgenic mice expressing human A53T α-synuclein, a mutation associated with familial, early-onset PD, had accumulation of insoluble phosphorylated α-synuclein in the ENS [45], decreased stool frequency and fecal water content [46,47] and increased α-synuclein protein and transcript levels in the colon [47]. Although changes in enteric α-synuclein were not reported for the nonhuman primate systemic MPTP model [34], analysis at varying timepoints in neurotoxin-induced rodent models of PD has produced diverse results.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxin-Induced Catecholaminergic Loss in the Colonic Myenteric Plexus of Rhesus Monkeys

Shultz

Resnikoff

Bondarenko

et al. 2016

J Alzheimers Dis Parkinsonism

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“…Indeed Lewy bodies and neurites, i.e., the misfolded ␣-synuclein that is a histological hallmark of PD, are found in vagal motor nuclei as well as in the ENS of patients with PD (6,35,55). Furthermore, the delayed emptying of solids observed in patients with PD (19) may indicate vagal degeneration, and ␣-synuclein-mutant mice show that the presence of ␣-synuclein in vagal efferent fibers decreases with age in a manner that is similar to the deterioration of GI motility observed in PD (39).…”

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confidence: 94%

Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis

Toti

Travagli

2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Toti L, Travagli RA. Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis. Am J Physiol Gastrointest Liver Physiol 307: G1013-G1023, 2014. First published October 2, 2014; doi:10.1152/ajpgi.00258.2014.-Idiopathic Parkinson's disease (PD) is a late-onset, chronic, and progressive motor dysfunction attributable to loss of nigrostriatal dopamine neurons. Patients with PD experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-hydroxy-dopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a Ͼ90% decrease in tyrosine hydroxylase-immunoreactivity (IR) on the injection site. The [13 C]-octanoic acid breath test showed a delayed gastric emptying 4 wk after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by the fourth ventricular application of either a combination of ␣1-and ␣2-or a combination of D1 and D2 receptor antagonists. Conversely, in 6-OHDA-treated rats, whereas DVC microinjection of tyramine had reduced effects on gastric tone or motility, DVC microinjection of thyrotropin-releasing hormone induced a similar increase in motility as in control rats. In 6-OHDA-treated rats, there was a decreased expression of choline acetyl transferase (ChAT)-IR and neuronal nitric oxide synthase (NOS)-IR in DVC neurons but an increase in dopamine-␤-hydroxylase-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach, and duodenum, there were no changes in the total number of neurons; however, the percentage of NOS-IR neurons increased, whereas that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis.brainstem; gastric motility; immunohistochemistry; Parkinson's disease IDIOPATHIC PARKINSON'S DISEASE (PD) is generally considered a movement disorder characterized by bradykinesia, rigidity, tremor, and gait/postural disorders related to the severe degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the basal ganglia. Although the movement disorder has dominated the attention of clinicians and researchers, it is becoming increasingly recognized that PD also involves a prominent nonmotor pathology. In fact, patients with PD experience a remarkably broad spectrum of prodromic nonmotor symptoms that include sleep disorders, orthostatic hypotension, and gastrointestinal (GI) dysfunctions, all of which add significantly to the overall disability caused by PD (9,22,26,33,38,42).GI symptoms, such as dysphagia, nausea, delayed gastric emptying and dysmotility, and constipation, often precede ...

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Alpha-synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system

Cited by 74 publications

References 67 publications

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

Neurotoxin-Induced Catecholaminergic Loss in the Colonic Myenteric Plexus of Rhesus Monkeys

Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis

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