Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats

Abstract

Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson’s disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson’s disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson’s disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson’s disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson’s disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions.

Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas

“…Mechanistically, it has been proposed that the initial formation of misfolded α-Syn occurs in the gut and then spreads to the brain via peripheral autonomic nerves, thus affecting several other organs, including the heart and intestine [ 153 ]. A recent study by the Van Den Berge group, using rats as an experimental model system, demonstrated marked age-dependent gut-to-brain and brain-to-gut spreading of α-Syn pathology along the sympathetic and parasympathetic nerves, and age-dependent dysfunction of the heart and stomach, as in patients with Parkinson’s disease [ 154 ]. Accordingly, it has been reported that trans-neuronal propagation of α-Syn pathology leads to sensory neuron dysfunction and neuropathic impairment, suggesting one of the pathogenic mechanisms underlying PD [ 155 ].…”

Characteristics of Autonomic Dysfunction in Parkinson’s Disease: A Large Chinese Multicenter Cohort Study

“…Despite the considerable understanding of PD symptoms, the exact pathogenesis of AutD is still largely unknown. Studies that demonstrate neuronal loss and abnormal aggregation of α-synuclein in the autonomic nervous system, including the dorsal motor nucleus of the vagus and sympathetic ganglia, may provide a pathological explanation for PD ( Gelpi et al, 2014 ; Van Den Berge et al, 2021 ).…”

Glutathione and Related Molecules in Parkinsonism

“…Nonmotor symptoms including constipation caused by gastrointestinal legions in PD precede motor symptoms by 10-20 years. Therefore, it is hypothesized that α-synuclein fibrils in PD pathology are formed initially in the ENS or sensory nervous system, before spreading in a prion-like fashion from the ENS to the CNS, in part via the vagal nerve [66][67][68][69][70]. Furthermore, bidirectional gut-to-brain and brain-to-gut transmission patterns of α-synuclein have been proposed, and the former pattern depends on gut environmental factors including the microbiota, which elicit mucosal inflammation, oxidative stress, and protein accumulation [71][72][73][74][75].…”