Age-dependent aggregation of α-synuclein in the nervous system of gut-brain axis is associated with caspase-1 activation

alpha-Synuclein (alpha-Syn) plays a key role in the development of Parkinson' desease (PD). As aging is acknowledged to be the greatest risk factor for PD, here we investigated alpha-Syn expression in the ileum, thoracic spinal cord, and midbrain of young (1-month-old), middle-aged (6-, 12-month-old) to old (18-month-old) mice. We demonstrated that both the levels of alpha-Syn monomers, oligomers and ratios of oligomers to monomers were increased with aging in the ileum, thoracic spinal cord, and midbrain. Whereas, the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, was decreased with aging in the midbrain. We failed to find corresponding alpha-Syn mRNA increase with aging. However, we found an increased expression of caspase-1 in the ileum, thoracic spinal cord, and midbrain. A specific caspase-1 inhibitor VX765 significantly reduced levels of both the alpha-Syn monomers and oligomers triggered by the rotenone in vitro. Taken together, the increase in alpha-Syn aggregation with aging might not occur first in the gut, but simultaneously in the nervous system of gut-brain axis. The mechanism of the age-dependent aggregation of alpha-Syn in nervous system is likely triggered by the aging-related caspase-1 activation.