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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Impairment of mitochondria dynamics by human A53T alpha-synuclein and rescue by NAP (davunetide) in a cell model for Parkinson's disease

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Autor(es):
Melo, T. Q. ; van Zomeren, K. C. ; Ferrari, M. F. R. ; Boddeke, H. W. G. M. ; Copray, J. C. V. M.
Número total de Autores: 5
Tipo de documento: Artigo Científico
Fonte: Experimental Brain Research; v. 235, n. 3, p. 731-742, MAR 2017.
Citações Web of Science: 7
Resumo

The formation of oligomers and aggregates of overexpressed or mutant alpha-synuclein play a role in the degeneration of dopaminergic neurons in Parkinson's disease by causing dysfunction of mitochondria, reflected in their disturbed mobility and production of ROS. The mode of action and mechanisms underlying this mitochondrial impairment is still unclear. We have induced stable expression of wild-type, A30P or A53T alpha-synuclein in neuronally differentiated SH-SY5Y neuroblastoma cells and studied anterograde and retrograde mitochondrial trafficking in this cell model for Parkinson's disease. In contrast to wild-type and A30P, A53T alpha-synuclein significantly inhibited mitochondrial trafficking, at first retrogradely and in a later stage anterogradely. Accordingly, A53T alpha-synuclein also caused the highest increase in ROS production in the dysmobilized mitochondria in comparison to wild-type or A30P alpha-synuclein. Treatment with NAP, the eight amino acid peptide identified as the active component of activity-dependent neuroprotective protein (ADNP), completely annihilated the adverse effects of A53T on mitochondrial dynamics. Our results reveal that A53T alpha-synuclein (oligomers or aggregates) leads to the inhibition of mitochondrial trafficking, which can be rescued by NAP, suggesting the involvement of microtubule disruption in the pathophysiology of Parkinson's disease. (AU)

Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
Beneficiário:Mayana Zatz
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 12/15495-2 - Tráfego mitocondrial e autofagocitose em neurônios dopaminérgicos humanos derivados de células-tronco embrionárias e de pluripotência induzida
Beneficiário:Merari de Fátima Ramires Ferrari
Linha de fomento: Auxílio à Pesquisa - Regular