A Conjugate of Aminoadamantane and Tetrahydro-γ-Carboline Inhibits Accumulation of Mutant α-Synuclein A53T in the Cellular Model of Proteinopathy.
A Conjugate of Aminoadamantane and Tetrahydro-γ-Carboline Inhibits Accumulation of Mutant α-Synuclein A53T in the Cellular Model of Proteinopathy.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Chernogolovka, RU · Author affiliation
Institute of Physiologically Active Compounds, Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia.Location evidence
Moscow, RU · Author affiliation
Institute of Physiologically Active Compounds, Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia.Location evidence
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Original abstract
Pathological aggregation of α-synuclein is a key event in the development of synucleinopathies, such as Parkinson's disease and Lewy body dementia. Currently, no effective disease-modifying therapy is available, necessitating the search for new therapeutic agents. One promising strategy involves the use of low-molecular-weight compounds capable of inhibiting the formation of toxic protein aggregates. This study evaluates the anti-aggregation properties of EC3222x, a conjugate of pharmacophoric fragments of amantadine and a fluorinated derivative of tetrahydro-γ-carboline. α-Synucleinopathy was modeled in the SH-SY5Y neuroblastoma cell line by transfection with a plasmid vector encoding the mutant human α-synuclein A53T protein. EC3222x at a concentration of 1 µM reduced the number of cells with α-synuclein A53T aggregates. Its efficacy was comparable to that of SynuClean-D and Buntanetap, known inhibitors of α-synuclein aggregation. Treatment with EC3222x reduced both the level of diffusely distributed intracellular α-synuclein and the formation of mature fibrillar aggregates and large aggresomes. Importantly, EC3222x did not affect the accumulation of another aggregation-prone protein, TDP-43, in a similar cellular model, indicating its specificity for α-synuclein. These findings suggest that EC3222x may represent a promising candidate for the development of therapeutic agents targeting synucleinopathies.