Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-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.

Acid β‐glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter α‐synuclein processing

“…It will be important to determine whether neuronal transgenes encoding WT human GBA can effectively lower the concentration of endogenous Snca in rodent brain or of exogenous SNCA in humanized mouse models. 28,41 If the interpretation of our mouse results (in Fig 3) is correct and can be confirmed by other investigators in independent studies, then its impact could be comparable to the effect of Rep1 expansion in SNCA alleles (see Fig 6). Cronin et al recently determined that upon expansion, the Rep1 enhancer element elevates the SNCA protein level in the brain to 125%.…”

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

“…Furthermore, neuropathological analyses indicate that alpha-synuclein pathology can occur very early in myenteric neurons in PD, prompting the provocative hypothesis that the pathological process could start in the gut [32,33]. Our data in Thy1-aSyn mice [53] indicated for the first time that alpha-synuclein over-expression is sufficient to induce colonic deficits, an observation later confirmed in other lines of mice [56]. However, neither study addressed if the digestive deficits are of central or peripheral origin, and this question remains unanswered.…”

α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease

“…In wild-type (CCK-GFP) mice, α-synuclein staining was detected within some CCK cells but could not easily be visualized in the enteric nerves (Supplemental Figure 4). The striking difference in immunofluorescence intensity between A53T and wild-type mouse intestine could be attributed to higher levels of α-synuclein in A53T mice (41). It is also possible that the human protein is recognized better by the primary antibody used in these experiments.…”