SYNC
Syncoilin (Syncoilin intermediate filament 1) (Syncoilin-1) [SYNC1]
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This experiment assessed normative expression patterns of alpha-synuclein (SYNC), including ganglionic remodeling and development of SYNC pathologies, in the submucosal plexus (SMP) of the colon during healthy aging. The observations address age-associated changes in bowel function and are relevant to evaluations of SMP-containing colonic biopsies for SYNC or synucleinopathies associated with aging and peripheral neurodegenerative diseases. Colonic submucosal whole mounts from groups of virgin male Fischer 344 rats (n ≥ 8 per group) at 4, 8, 16, and 24 months of age were processed immunohistochemically for SYNC and the pan-neuronal marker HuC/D. In addition, macrophages immunoreactive for MHCII were examined. Stereological protocols were used to generate unbiased estimates of neuron density, neurons per ganglion, neurons per ganglionic area, and neuron size. The protein SYNC was expressed in a subpopulation of SMP neurons, in both nucleus and cytoplasm. The general age-associated pattern across different cell counts was an increase in the number of SYNC neurons between 4 and 8 months of age, with progressively decreasing numbers of both SYNC and SYNC- neurons over the remaining lifespan. The soma size of SYNC neurons increased progressively with age. Aggregated SYNC occurred in the aging SMP, and macrophages with alternatively activated profiles were located adjacent to pathological SYNC deposits, consistent with ongoing phagocytosis. Changes in SYNC expression with age, including a baseline of accumulating synucleinopathies in the healthy aging SMP, need to be considered when interpreting either functional disturbances or biopsies of the aging colon.
MeSH Terms
- Aging
- Animals
- Biopsy
- Colon
- Immunohistochemistry
- Male
- Neurodegenerative Diseases
- Rats
- Rats, Inbred F344
- Submucous Plexus
- alpha-Synuclein
Keywords
- MHCII
- Parkinson's disease
- calbindin
- colon
- enteric
With age, alpha-synuclein (α-SYNC) misfolds and forms insoluble deposits of protein in the myenteric plexus, leading presumably to dystrophy and degeneration in the circuitry controlling gastrointestinal (GI) function. The present experiment examined aggregates of α-SYNC in the aging small intestine and investigated how macrophages in the wall of the GI tract respond to these aberrant deposits. Groups of adult and aged Fisher 344 rats were studied. Whole mounts of duodenal, jejunal, and ileal smooth muscle wall, including the myenteric plexus, were prepared. Double labeling immunohistochemistry was used to stain α-SYNC protein and the phenotypic macrophage antigens CD163 and MHCII. Alpha-synuclein accumulated in dense aggregates in axons of both postganglionic and preganglionic neurons throughout the small intestine. Staining patterns suggested that deposits of protein occur initially in axonal terminals and then spread retrogradely toward the somata. Macrophages that were adjacent to dystrophic terminal processes were swollen and contained vacuoles filled with insoluble α-SYNC, and these macrophages commonly had the phenotype of alternatively activated phagocytes. The present results suggest that macrophages play an active phagocytotic role in removing α-SYNC aggregates that accumulate with age in the neural circuitry of the gut. Our observations further indicate that this housekeeping response does not clear the protein sufficiently to eliminate all synucleinopathies or their precursor aggregates from the healthy aging GI tract. Thus, accumulating deposits of insoluble α-SYNC in the wall of the GI tract may contribute, especially when compounded by disease or inflammation, to the age-associated neuropathies in the gut that compromise GI function.
MeSH Terms
- Age Factors
- Aging
- Animals
- Antigens, CD
- Antigens, Differentiation, Myelomonocytic
- Autonomic Fibers, Postganglionic
- Autonomic Fibers, Preganglionic
- Biomarkers
- Histocompatibility Antigens Class II
- Immunohistochemistry
- Intestine, Small
- Macrophage Activation
- Macrophages
- Male
- Muscle, Smooth
- Myenteric Plexus
- Phagocytosis
- Phenotype
- Protein Folding
- Rats
- Rats, Inbred F344
- Receptors, Cell Surface
- alpha-Synuclein