JM-20, a Benzodiazepine-Dihydropyridine Hybrid Molecule, Inhibits the Formation of Alpha-Synuclein-Aggregated Species

Santos, Cleonice Creusa dos; Cardim-Pires, Thyago R.; Shvachiy, Liana; Fonseca-Fonseca, Luis Arturo; Muñoz, Patricia; Costa, Ana Carla S; Teles-Souza, Jéssica; Ochoa-Rodríguez, Estael; Costa, Maria de Fátima Dias; Palhano, Fernando L.; Segura‐Aguilar, Juan; Barbosa, Deyse Brito; Bomfim, Mayra Ramos do; Santos, Manoelito Coelho dos; Leite, Franco Henrique Andrade; Pita, Samuel Silva da Rocha; Costa, Sílvia Lima; Nuñez-Figueredo, Yanier; Outeiro, Tiago F.; Foguel, Débora; Silva, Víctor Diógenes Amaral da

doi:10.1007/s12640-022-00559-7

Cited by 6 publications

(2 citation statements)

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“…As an initial test, we checked if the different cell lines used in the present study formed aggregates when transfected with α-synuclein-T and V5-synphilin-1 (SynT/Sph1 model). As the model has been mostly applied in H4 neuroglioma cell line and modifications of it in SH-SY5Y 36 , 38 , we assessed if the inclusions formed are indeed α-synuclein aggregates. We initially performed thioflavin S (ThS) staining combined with immunofluorescence for α-synuclein and V5 (tagged to synphilin-1) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These experimental groups were used in two main types of experiments. First, to assess changes in the presence and quantity of aggregates, we used an α-synuclein aggregation model termed α-synuclein-T/V5-synphilin-1 (SynT/Sph1); this model (detailed below) has already been used for the assessment of the effects of different drugs on α-synuclein aggregation 36 , 38 , 40 . Second, the aggregate-like nature of the inclusions was determined with thioflavin S-staining (ThS).…”

Section: Methodsmentioning

confidence: 99%

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Angiotensin type 1 receptor activation promotes neuronal and glial alpha-synuclein aggregation and transmission

Lage,

Rodriguez-Perez,

Villar-Cheda

et al. 2024

npj Parkinsons Dis.

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The brain renin-angiotensin system (RAS) has been related to dopaminergic degeneration, and high expression of the angiotensin II (AngII) type 1 receptor (AT1) gene is a marker of the most vulnerable neurons in humans. However, it is unknown whether AngII/AT1 overactivation affects α-synuclein aggregation and transmission. In vitro, AngII/AT1 activation increased α-synuclein aggregation in dopaminergic neurons and microglial cells, which was related to AngII-induced NADPH-oxidase activation and intracellular calcium raising. In mice, AngII/AT1 activation was involved in MPTP-induced increase in α-synuclein expression and aggregation, as they significantly decreased in mice treated with the AT1 blocker telmisartan and AT1 knockout mice. Cell co-cultures (transwells) revealed strong transmission of α-synuclein from dopaminergic neurons to astrocytes and microglia. AngII induced a higher α-synuclein uptake by microglial cells and an increase in the transfer of α-synuclein among astroglial cells. However, AngII did not increase the release of α-synuclein by neurons. The results further support brain RAS dysregulation as a major mechanism for the progression of Parkinson’s disease, and AT1 inhibition and RAS modulation as therapeutic targets.

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Section: Resultsmentioning

confidence: 99%