Abstract:
:Alpha-synuclein (αSyn) preformed fibrils (PFF) induce endogenous αSyn aggregation leading to reduced synaptic transmission. Neuronal activity modulates release of αSyn; however, whether neuronal activity regulates the spreading of αSyn pathology remains elusive. Here, we established a hippocampal slice culture system from wild-type (WT) mice and found that both Ca2+ influx and the uptake of αSyn PFF were higher in the CA3 than in the CA1 sub-region. Pharmacologically enhancing neuronal activity substantially increased αSyn pathology in αSyn PFF-treated hippocampal or midbrain slice cultures and accelerated dopaminergic neuron degeneration. Consistently, neuronal hyperactivity promoted PFF trafficking along axons/dendrites within microfluidic chambers. Unexpectedly, enhancing neuronal activity in LRRK2 G2019S mutant slice cultures further increased αSyn pathology, especially with more Lewy body (LB) forming than in WT slice cultures. Finally, following injection of αSyn PFF and chemogenetic modulators into the dorsal striatum of WT mice, both motor behavior and αSyn pathology were exacerbated likely by enhancing neuronal activity, since they were ameliorated by reducing neuronal activity. Thus, a greater understanding of the impact of neuronal activity on αSyn aggregation and spreading, as well as dopaminergic neuronal vulnerability, may provide new therapeutic strategies for patients with LB disease (LBD).
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Wu Q,Shaikh MA,Meymand ES,Zhang B,Luk KC,Trojanowski JQ,Lee VMdoi
10.1007/s00401-020-02227-6subject
Has Abstractpub_date
2020-12-01 00:00:00pages
831-849issue
6eissn
0001-6322issn
1432-0533pii
10.1007/s00401-020-02227-6journal_volume
140pub_type
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