Abstract
α-Synuclein (α-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 α-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 α-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 α-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 α-Syn monomers and oligomers triggered by the rotenone in vitro. Taken together, the increase in α-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 α-Syn in nervous system is likely triggered by the aging-related caspase-1 activation.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder, which is characterized by the death of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies (LBs) and Lewy neurites (LNs) as cytosolic inclusions in surviving neurons
Α-Syn is associated with the pathogenesis of PD(Goedert, 2001), as several mutations associated with the early onset of PD are found in this protein (e.g. A30P(Kruger et al, 1998), E46K(Zarranz et al, 2004) and A53T(Polymeropoulos et al, 1997), which are known to the scientific community for relatively long time, and several more recently discovered H50Q(Appel-Cresswell et al, 2013; Proukakis et al, 2013), G51D(Kiely et al, 2013; Lesage et al, 2013), and A53E(Pasanen et al, 2014) mutants). α-Syn is a widespread neuronal presynaptic protein located in the nervous system, and with lower expression in blood cells, pancreas, heart, and skeletal muscle(Brighina et al, 2010; Ltic et al, 2004)
As growing evidence suggesting that PD affects the gut and the incidences of the debilitating digestive symptoms may partly be explained by the presence of inclusions and debris immunoreactive for α-Syn in the enteric nervous system [26], the α-Syn accumulation was evaluated in the enteric nervous system with aging and immunofluorescence analysis of samples from the 1, 6, 12, and 18-month-old mice was performed
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder, which is characterized by the death of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies (LBs) and Lewy neurites (LNs) as cytosolic inclusions in surviving neurons. Accumulated evidence suggests that α-Syn does not have a unique biological function, but instead it serves as an illustrative example of multifunctional intrinsically disordered protein(Breydo et al, 2012; Silva et al, 2013; Uversky, 2017). Given that the abundance of α-Syn in the presynaptic nerve terminals and its ability to bind to lipid membranes, this protein may play a critical role in in neural transmission(Davidson et al, 1998), the release of neurotransmitters, neuronal plasticity, learning and development(Krainc et al, 2017). Α-Syn is a heat-stable soluble protein binding several other proteins, which can promote conformational changes of physiological relevance or lead to abnormal aggregation as well(Breydo et al, 2012; Silva et al, 2013; Uversky, 2017)
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