The small GTPase Rab11 co-localizes with α-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity

Oldriska Chutna, Susana Gonçalves, Anna Villar-Piqué, Patrícia Guerreiro, Zrinka Marijanovic, Tiago Mendes, José Ramalho, Evangelia Emmanouilidou, Salvador Ventura, Jochen Klucken, Duarte C. Barral, Flaviano Giorgini, Kostas Vekrellis, Tiago F. Outeiro

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Alpha-synuclein (aSyn) misfolding and aggregation are pathological features common to several neurodegenerative diseases, including Parkinson's disease (PD). Mounting evidence suggests that aSyn can be secreted and transferred from cell to cell, participating in the propagation and spreading of pathological events. Rab11, a small GTPase, is an important regulator in both endocytic and secretory pathways. Here, we show that Rab11 is involved in regulating aSyn secretion. Rab11 knockdown or overexpression of either Rab11a wild-type (Rab11a WT) or Rab11a GDP-bound mutant (Rab11a S25N) increased secretion of aSyn. Furthermore, we demonstrate that Rab11 interacts with aSyn and is present in intracellular inclusions together with aSyn. Moreover, Rab11 reduces aSyn aggregation and toxicity. Our results suggest that Rab11 is involved in modulating the processes of aSyn secretion and aggregation, both of which are important mechanisms in the progression of aSyn pathology in PD and other synucleinopathies.

Original languageEnglish
Pages (from-to)6732-6745
Number of pages14
JournalHuman molecular genetics
Volume23
Issue number25
DOIs
Publication statusPublished - 20 Dec 2014

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Synucleins
alpha-Synuclein
Monomeric GTP-Binding Proteins
Parkinson Disease
Secretory Pathway
Neurodegenerative Diseases
Pathology

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Chutna, Oldriska ; Gonçalves, Susana ; Villar-Piqué, Anna ; Guerreiro, Patrícia ; Marijanovic, Zrinka ; Mendes, Tiago ; Ramalho, José ; Emmanouilidou, Evangelia ; Ventura, Salvador ; Klucken, Jochen ; Barral, Duarte C. ; Giorgini, Flaviano ; Vekrellis, Kostas ; Outeiro, Tiago F. / The small GTPase Rab11 co-localizes with α-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity. In: Human molecular genetics. 2014 ; Vol. 23, No. 25. pp. 6732-6745.
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abstract = "Alpha-synuclein (aSyn) misfolding and aggregation are pathological features common to several neurodegenerative diseases, including Parkinson's disease (PD). Mounting evidence suggests that aSyn can be secreted and transferred from cell to cell, participating in the propagation and spreading of pathological events. Rab11, a small GTPase, is an important regulator in both endocytic and secretory pathways. Here, we show that Rab11 is involved in regulating aSyn secretion. Rab11 knockdown or overexpression of either Rab11a wild-type (Rab11a WT) or Rab11a GDP-bound mutant (Rab11a S25N) increased secretion of aSyn. Furthermore, we demonstrate that Rab11 interacts with aSyn and is present in intracellular inclusions together with aSyn. Moreover, Rab11 reduces aSyn aggregation and toxicity. Our results suggest that Rab11 is involved in modulating the processes of aSyn secretion and aggregation, both of which are important mechanisms in the progression of aSyn pathology in PD and other synucleinopathies.",
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Chutna, O, Gonçalves, S, Villar-Piqué, A, Guerreiro, P, Marijanovic, Z, Mendes, T, Ramalho, J, Emmanouilidou, E, Ventura, S, Klucken, J, Barral, DC, Giorgini, F, Vekrellis, K & Outeiro, TF 2014, 'The small GTPase Rab11 co-localizes with α-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity', Human molecular genetics, vol. 23, no. 25, pp. 6732-6745. https://doi.org/10.1093/hmg/ddu391

The small GTPase Rab11 co-localizes with α-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity. / Chutna, Oldriska; Gonçalves, Susana; Villar-Piqué, Anna; Guerreiro, Patrícia; Marijanovic, Zrinka; Mendes, Tiago; Ramalho, José; Emmanouilidou, Evangelia; Ventura, Salvador; Klucken, Jochen; Barral, Duarte C.; Giorgini, Flaviano; Vekrellis, Kostas; Outeiro, Tiago F.

In: Human molecular genetics, Vol. 23, No. 25, 20.12.2014, p. 6732-6745.

Research output: Contribution to journalArticle

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T1 - The small GTPase Rab11 co-localizes with α-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity

AU - Chutna, Oldriska

AU - Gonçalves, Susana

AU - Villar-Piqué, Anna

AU - Guerreiro, Patrícia

AU - Marijanovic, Zrinka

AU - Mendes, Tiago

AU - Ramalho, José

AU - Emmanouilidou, Evangelia

AU - Ventura, Salvador

AU - Klucken, Jochen

AU - Barral, Duarte C.

AU - Giorgini, Flaviano

AU - Vekrellis, Kostas

AU - Outeiro, Tiago F.

PY - 2014/12/20

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N2 - Alpha-synuclein (aSyn) misfolding and aggregation are pathological features common to several neurodegenerative diseases, including Parkinson's disease (PD). Mounting evidence suggests that aSyn can be secreted and transferred from cell to cell, participating in the propagation and spreading of pathological events. Rab11, a small GTPase, is an important regulator in both endocytic and secretory pathways. Here, we show that Rab11 is involved in regulating aSyn secretion. Rab11 knockdown or overexpression of either Rab11a wild-type (Rab11a WT) or Rab11a GDP-bound mutant (Rab11a S25N) increased secretion of aSyn. Furthermore, we demonstrate that Rab11 interacts with aSyn and is present in intracellular inclusions together with aSyn. Moreover, Rab11 reduces aSyn aggregation and toxicity. Our results suggest that Rab11 is involved in modulating the processes of aSyn secretion and aggregation, both of which are important mechanisms in the progression of aSyn pathology in PD and other synucleinopathies.

AB - Alpha-synuclein (aSyn) misfolding and aggregation are pathological features common to several neurodegenerative diseases, including Parkinson's disease (PD). Mounting evidence suggests that aSyn can be secreted and transferred from cell to cell, participating in the propagation and spreading of pathological events. Rab11, a small GTPase, is an important regulator in both endocytic and secretory pathways. Here, we show that Rab11 is involved in regulating aSyn secretion. Rab11 knockdown or overexpression of either Rab11a wild-type (Rab11a WT) or Rab11a GDP-bound mutant (Rab11a S25N) increased secretion of aSyn. Furthermore, we demonstrate that Rab11 interacts with aSyn and is present in intracellular inclusions together with aSyn. Moreover, Rab11 reduces aSyn aggregation and toxicity. Our results suggest that Rab11 is involved in modulating the processes of aSyn secretion and aggregation, both of which are important mechanisms in the progression of aSyn pathology in PD and other synucleinopathies.

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DO - 10.1093/hmg/ddu391

M3 - Article

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JO - Human molecular genetics

JF - Human molecular genetics

SN - 0964-6906

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