DDOX expands the repertoire of tetracyclines for Parkinson's disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils.

ABSTRACT: The increasing prevalence of Parkinson's disease (PD) requires innovative multi-targeted disease-modifying therapies to counteract the toxicity associated with the amplification, propagation, and accumulation of alpha-synuclein (α-Syn) aggregates in the brain. Tetracyclines, particularly doxycycline, have demonstrated multimodal neuroprotective effects, both in vitro and in vivo. The non-antibiotic derivative of doxycycline 4-dedimethylamino-12a-deoxydoxycycline (DDOX), has been recently shown to rescue neurons from oxidative injury. Here, we demonstrate that DDOX showcases a diverse range of mechanisms targeting α-Syn aggregates. Notably, DDOX inhibited the aggregation of α-Syn and the seeding ability of α-Syn pre-formed fibrils (PFF) in biophysical and cellular assays. In addition, the c

SUBMITTER: Teran MDM 

PROVIDER: S-EPMC12572218 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature