TY  - JOUR
AU  - Pinto-Costa, Rita
AU  - Harbachova, Eugenia
AU  - La Vitola, Pietro
AU  - Di Monte, Donato Antonio
TI  - Overexpression-Induced α-Synuclein Brain Spreading.
JO  - Neurotherapeutics
VL  - 20
IS  - 1
SN  - 1933-7213
CY  - New York, NY
PB  - Springer
M1  - DZNE-2022-01766
SP  - 83-96
PY  - 2023
AB  - Interneuronal transfer of pathological α-synuclein species is thought to play an important role in the progressive advancement of Lewy pathology and increasing severity of clinical manifestations in Parkinson's and other diseases commonly referred to as synucleinopathies. Pathophysiological conditions and mechanisms triggering this trans-synaptic spreading bear therefore significant pathogenetic implications but have yet to be fully elucidated. In vivo experimental models support the conclusion that increased expression of intraneuronal α-synuclein can itself induce protein spreading throughout the brain as well as from the brain to peripheral tissues. For example, overexpression of α-synuclein targeted to the rodent dorsal medulla oblongata results in its transfer and accumulation into recipient axons innervating this brain region; through these axons, α-synuclein can then travel caudo-rostrally and reach other brain sites in the pons, midbrain, and forebrain. When protein overexpression is induced in the rodent midbrain, long-distance α-synuclein spreading can be followed over time; spreading-induced α-synuclein accumulation affects lower brain regions, including the dorsal motor nucleus of the vagus, proceeds through efferent axons of the vagus nerve, and is ultimately detected within vagal motor nerve endings in the gastric wall. As discussed in this review, animal models featuring α-synuclein overexpression not only support a relationship between α-synuclein burden and protein spreading but have also provided important clues on conditions/mechanisms capable of promoting interneuronal α-synuclein transfer. Intriguing findings include the relationship between neuronal activity and protein spreading and the role of oxidant stress in trans-synaptic α-synuclein mobility.
KW  - Animals
KW  - alpha-Synuclein: metabolism
KW  - Brain: metabolism
KW  - Neurons: metabolism
KW  - Parkinson Disease: metabolism
KW  - Stomach: innervation
KW  - Stomach: metabolism
KW  - Synaptic Transmission: physiology
KW  - Synucleinopathies: metabolism
KW  - Vagus Nerve: metabolism
KW  - Vagus Nerve: physiology
KW  - alpha-Synuclein (NLM Chemicals)
KW  - Animal models (Other)
KW  - Gut-brain axis (Other)
KW  - Neuronal activity (Other)
KW  - Oxidative stress (Other)
KW  - Parkinson (Other)
KW  - Vagus nerve (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10119350
C6  - pmid:36512255
DO  - DOI:10.1007/s13311-022-01332-6
UR  - https://pub.dzne.de/record/169044
ER  -