TY  - JOUR
AU  - Van Den Berge, Nathalie
AU  - Ferreira, Nelson
AU  - Mikkelsen, Trine Werenberg
AU  - Alstrup, Aage Kristian Olsen
AU  - Tamgüney, Gültekin
AU  - Karlsson, Páll
AU  - Terkelsen, Astrid Juhl
AU  - Nyengaard, Jens Randel
AU  - Jensen, Poul Henning
AU  - Borghammer, Per
TI  - Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats
JO  - Brain
VL  - 144
IS  - 6
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - FZJ-2021-05890
SP  - 1853 - 1868
PY  - 2021
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:33880502
UR  - <Go to ISI:>//WOS:000710929200029
DO  - DOI:10.1093/brain/awab061
UR  - https://juser.fz-juelich.de/record/904320
ER  -