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Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes.

ABSTRACT: Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor signs in the gastrointestinal tract that include dysphagia, gastroparesis, prolonged gastrointestinal transit time, constipation and difficulty with defecation. The gastrointestinal dysfunction commonly precedes the motor symptoms by decades. Most PD is sporadic and of unknown etiology, but a fraction is familial. Among familial forms of PD, a small fraction is caused by missense (A53T, A30P and E46K) and copy number mutations in SNCA which encodes alpha-synuclein, a primary protein constituent of Lewy bodies, the pathognomonic protein aggregates found in neurons in PD. We set out to develop transgenic mice expressing mutant alpha-synuclein (either A53T or A30P) from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines show robust abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also has abnormal motor behavior but neither demonstrates cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions or neurodegeneration. These animals recapitulate the early gastrointestinal abnormalities seen in human PD. The animals also serve as an in vivo system in which to investigate therapies for reversing the neurological dysfunction that target alpha-synuclein toxicity at its earliest stages.

SUBMITTER: Kuo YM

PROVIDER: S-EPMC2850613 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes.

Kuo Yien-Ming YM Li Zhishan Z Jiao Yun Y Gaborit Nathalie N Pani Amar K AK Orrison Bonnie M BM Bruneau Benoit G BG Giasson Benoit I BI Smeyne Richard J RJ Gershon Michael D MD Nussbaum Robert L RL

Human molecular genetics 20100127 9

Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor signs in the gastrointestinal tract that include dysphagia, gastroparesis, prolonged gastrointestinal transit time, constipation and difficulty with defecation. The gastrointestinal dysfunction commonly precedes the motor symptoms by decades. Most PD is sporadic and of unknown etiology, but a fraction is familial. Among familial forms of PD, a small fraction is caused by missense (A53T, A30P and E46K) and copy ...[more]

PMID: 20106867

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Project description:BackgroundGastrointestinal dysfunction can affect Parkinson's disease (PD) patients long before the onset of motor symptoms. However, little is known about the relationship between gastrointestinal abnormalities and the development of PD. Contrary to other animal models, the human A53T alpha-synuclein (?S) transgenic mice, Line G2-3, develops ?S-driven neurological and motor impairments after 9?months of age, displaying a long presymptomatic phase free of central nervous system (CNS) dysfunction.MethodsTo determine whether this line can be suitable to study constipation as it occurs in prodromal PD, gastrointestinal functionality was assessed in young mice through a multidisciplinary approach, based on behavioral and biochemical analysis combined with electrophysiological recordings of mouse intestinal preparations.ResultsWe found that the A53T ?S mice display remarkable signs of gastrointestinal dysfunction that precede motor abnormalities and ?S pathology in the CNS by at least 6?months. Young ?S mice show a drastic delay in food transit along the gastrointestinal tract, of almost 2?h in 3?months old mice that increased to more than 3?h at 6?months. Such impairment was associated with abnormal formation of stools that resulted in less abundant but longer pellets excreted, suggesting a deficit in the intestinal peristalsis. In agreement with this, electrically evoked contractions of the colon, but not of the ileum, showed a reduced motor response in both longitudinal and circular muscle layers in ?S mice already at 3?months of age, that was mainly due to an impaired cholinergic transmission of the underlying enteric nervous system. Interestingly, the presence of insoluble and aggregated ?S was found in enteric neurons in both myenteric and submucosal plexi only in the colon of 3?months old ?S mice, but not in the small intestine, and exacerbated with age, mimicking the increase in transit delay and the contraction deficit showed by behavioral and electrical recordings data.ConclusionsGastrointestinal dysfunction in A53T ?S mice represents an early sign of ?S-driven pathology without concomitant CNS involvement. We believe that this model can be very useful to study disease-modifying strategies that could extend the prodromal phase of PD and halt ?S pathology from reaching the brain.

Project description:Alpha-synuclein (α-Syn) is widely distributed and involved in the regulation of the nervous system. The phosphorylation of α-Syn at serine 129 (pSer129α-Syn) is known to be closely associated with α-Synucleinopathies, especially Parkinson's disease (PD). The present study aimed to explore the α-Syn accumulation and its phosphorylation in the enteric nervous system (ENS) in patients without neurodegeneration. Patients who underwent colorectal surgery for either malignant or benign tumors that were not suitable for endoscopic resection (n = 19) were recruited to obtain normal intestinal specimens, which were used to assess α-Syn immunoreactivity patterns using α-Syn and pSer129α-Syn antibodies. Furthermore, the sub-location of α-Syn in neurons was identified by α-Syn/neurofilament double staining. Semi-quantitative counting was used to evaluate the expression of α-Syn and pSer129α-Syn in the ENS. Positive staining of α-Syn was detected in all intestinal layers in patients with non-neurodegenerative diseases. There was no significant correlation between the distribution of α-Syn and age (p = 0.554) or tumor stage (p = 0.751). Positive staining for pSer129α-Syn was only observed in the submucosa and myenteric plexus layers. The accumulation of pSer129α-Syn increased with age. In addition, we found that the degenerative changes of the ENS were related to the degree of tumor malignancy (p = 0.022). The deposits of α-Syn were present in the ENS of patients with non-neurodegenerative disorders; particularly the age-dependent expression of pSer129α-Syn in the submucosa and myenteric plexus. The current findings of α-Syn immunostaining in the ENS under near non-pathological conditions weaken the basis of using α-Syn pathology as a suitable hallmark to diagnose α-Synucleinopathies including PD. However, our data provided unique perspectives to study gastrointestinal dysfunction in non-neurodegenerative disorders. These findings provide new evidence to elucidate the neuropathological characteristics and α-Syn pathology pattern of the ENS in non-neurodegenerative conditions.

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Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes.

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Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes.

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