RT Journal Article
T1 Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms
A1 Lage Pita, Lucía
A1 Rodríguez Pérez, Ana Isabel
A1 Labandeira García, José Luis
A1 Domínguez Meijide, Antonio
K1 Alpha-synuclein
K1 Angiotensin
K1 Neurodegeneration
K1 Neuroinflammation
K1 Parkinson
K1 Rho-kinase
AB ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation and activation of survival signaling pathways, and clinical trials have been initiated. More recently, fasudil has been suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it is a consequence of direct binding of the fasudil molecule to α-synuclein. We studied the mechanisms involved in the effects of fasudil on α-synuclein aggregation using the α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were studied using real time quaking inducing conversion (RT-QuiC). Fasudil decreased the number of cells with inclusions and the size of inclusions in dopaminergic neurons and glial cells, and inhibited α-synuclein aggregation and microglial endocytosis of aggregates. These changes were not due to changes in α-synuclein protein expression or phosphorylation and were related to ROCK inhibition rather than direct interaction with α-synuclein, as confirmed with a second ROCK inhibitor (Y27632) and ROCK gene silencing. We observed that ROCK inhibition downregulates several factors that are known to promote α-synuclein aggregation such as NADPH-oxidase-derived oxidative stress, intracellular calcium increase, and α-synuclein endocytosis, and promotes autophagy. The present results support that fasudil is a useful drug against Parkinson's disease progression. In addition to other reported neuroprotective properties, fasudil inhibits α-synuclein aggregation and microglial endocytosis of aggregates, which enhances the microglial inflammatory response. The effects of fasudil are mostly related to ROCK inhibition, which we have shown using two structurally different ROCK inhibitors and knockdown data, and further supported by using RT-QuiC.
PB Elsevier
SN 1933-7213
YR 2025
FD 2025
LK https://hdl.handle.net/10347/42392
UL https://hdl.handle.net/10347/42392
LA eng
NO Neurotherapeutics Volume 22, Issue 2, March 2025, e00544
NO This work was supported by the Spanish Ministry of Science and Innovation (PID2021-126848NB-I00; PLEC2022-009401; PID2023-150743OB-I00), Instituto de Salud Carlos III (RD21/0017/0031 and CIBERNED), Galician Government (XUGA, ED431C 2022/41) and FEDER (Regional European Development Fund).
DS Minerva
RD 23 may 2026