Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy

Dominik M. Haddad; Sven Vilain; Melissa Vos; Giovanni Esposito; Samer Matta; Vera M. Kalscheuer; Katleen Craessaerts; Maarten Leyssen; Rafaella M.P. Nascimento; Angela M. Vianna-Morgante; Bart DeStrooper; Hilde VanEsch; Vanessa A. Morais; Patrik Verstreken

doi:10.1016/j.molcel.2013.04.012

Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy

Dominik M. Haddad, Sven Vilain, Melissa Vos, Giovanni Esposito, Samer Matta, Vera M. Kalscheuer, Katleen Craessaerts, Maarten Leyssen, Rafaella M.P. Nascimento, Angela M. Vianna-Morgante, Bart DeStrooper, Hilde VanEsch, Vanessa A. Morais^*, Patrik Verstreken

^*Corresponding author for this work

Institute of Neurogenetics

78 Citations (Scopus)

Abstract

The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using invitro and invivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function.

Original language	English
Journal	Molecular Cell
Volume	50
Issue number	6
Pages (from-to)	831-843
Number of pages	13
ISSN	1097-2765
DOIs	https://doi.org/10.1016/j.molcel.2013.04.012
Publication status	Published - 27.06.2013

Funding

We thank the Bloomington and VDRC stock centers; Kyoung Sang Cho, Willy Baarends, and Konstanze Winklhofer for reagents; and Bassem Hassan, Wim Vandenberghe, and members of the Verstreken and De Strooper labs for comments. V.M.K. is financed by a grant of the German Ministry of Education and Research through the MRNET and by the Project GENCODYS (241995), which is funded by the European Union Framework Program 7 (FP7); S.V. and M.L. are supported by an FWO postdoctoral fellowship; and M.V. is supported by an IWT predoctoral fellowship and a PDM postdoctoral fellowship by the research fund KU Leuven. Support to P.V. was provided by a Marie Curie Excellence Grant (MEXT-CT-2006-042267), an ERC Starting Grant (260678), the Research Foundation Flanders (FWO grants G053913, G079013, G095511, and G074709), a Methusalem grant of the Flemish Government, the Francqui Foundation, the Hercules Foundation (AKUL/09/037), the Instutuut voor Wetenschap en Technologie (IWT), the Interuniversity Attraction Pole program by BELSPO (IAP P7/16 NEUROBRAINNET), the research fund KU Leuven (OT Start, GOA/13/017), and VIB.

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Haddad, D. M., Vilain, S., Vos, M., Esposito, G., Matta, S., Kalscheuer, V. M., Craessaerts, K., Leyssen, M., Nascimento, R. M. P., Vianna-Morgante, A. M., DeStrooper, B., VanEsch, H., Morais, V. A., & Verstreken, P. (2013). Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy. Molecular Cell, 50(6), 831-843. https://doi.org/10.1016/j.molcel.2013.04.012

@article{f64d8cef0eec40b38c41923ffe1cbf7b,

title = "Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy",

abstract = "The prevalence of intellectual disability is around 3\%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using invitro and invivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function.",

author = "Haddad, \{Dominik M.\} and Sven Vilain and Melissa Vos and Giovanni Esposito and Samer Matta and Kalscheuer, \{Vera M.\} and Katleen Craessaerts and Maarten Leyssen and Nascimento, \{Rafaella M.P.\} and Vianna-Morgante, \{Angela M.\} and Bart DeStrooper and Hilde VanEsch and Morais, \{Vanessa A.\} and Patrik Verstreken",

note = "Funding Information: We thank the Bloomington and VDRC stock centers; Kyoung Sang Cho, Willy Baarends, and Konstanze Winklhofer for reagents; and Bassem Hassan, Wim Vandenberghe, and members of the Verstreken and De Strooper labs for comments. V.M.K. is financed by a grant of the German Ministry of Education and Research through the MRNET and by the Project GENCODYS (241995), which is funded by the European Union Framework Program 7 (FP7); S.V. and M.L. are supported by an FWO postdoctoral fellowship; and M.V. is supported by an IWT predoctoral fellowship and a PDM postdoctoral fellowship by the research fund KU Leuven. Support to P.V. was provided by a Marie Curie Excellence Grant (MEXT-CT-2006-042267), an ERC Starting Grant (260678), the Research Foundation Flanders (FWO grants G053913, G079013, G095511, and G074709), a Methusalem grant of the Flemish Government, the Francqui Foundation, the Hercules Foundation (AKUL/09/037), the Instutuut voor Wetenschap en Technologie (IWT), the Interuniversity Attraction Pole program by BELSPO (IAP P7/16 NEUROBRAINNET), the research fund KU Leuven (OT Start, GOA/13/017), and VIB. ",

year = "2013",

month = jun,

day = "27",

doi = "10.1016/j.molcel.2013.04.012",

language = "English",

volume = "50",

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journal = "Molecular Cell",

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Haddad, DM, Vilain, S, Vos, M, Esposito, G, Matta, S, Kalscheuer, VM, Craessaerts, K, Leyssen, M, Nascimento, RMP, Vianna-Morgante, AM, DeStrooper, B, VanEsch, H, Morais, VA & Verstreken, P 2013, 'Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy', Molecular Cell, vol. 50, no. 6, pp. 831-843. https://doi.org/10.1016/j.molcel.2013.04.012

TY - JOUR

T1 - Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy

AU - Haddad, Dominik M.

AU - Vilain, Sven

AU - Vos, Melissa

AU - Esposito, Giovanni

AU - Matta, Samer

AU - Kalscheuer, Vera M.

AU - Craessaerts, Katleen

AU - Leyssen, Maarten

AU - Nascimento, Rafaella M.P.

AU - Vianna-Morgante, Angela M.

AU - DeStrooper, Bart

AU - VanEsch, Hilde

AU - Morais, Vanessa A.

AU - Verstreken, Patrik

N1 - Funding Information: We thank the Bloomington and VDRC stock centers; Kyoung Sang Cho, Willy Baarends, and Konstanze Winklhofer for reagents; and Bassem Hassan, Wim Vandenberghe, and members of the Verstreken and De Strooper labs for comments. V.M.K. is financed by a grant of the German Ministry of Education and Research through the MRNET and by the Project GENCODYS (241995), which is funded by the European Union Framework Program 7 (FP7); S.V. and M.L. are supported by an FWO postdoctoral fellowship; and M.V. is supported by an IWT predoctoral fellowship and a PDM postdoctoral fellowship by the research fund KU Leuven. Support to P.V. was provided by a Marie Curie Excellence Grant (MEXT-CT-2006-042267), an ERC Starting Grant (260678), the Research Foundation Flanders (FWO grants G053913, G079013, G095511, and G074709), a Methusalem grant of the Flemish Government, the Francqui Foundation, the Hercules Foundation (AKUL/09/037), the Instutuut voor Wetenschap en Technologie (IWT), the Interuniversity Attraction Pole program by BELSPO (IAP P7/16 NEUROBRAINNET), the research fund KU Leuven (OT Start, GOA/13/017), and VIB.

PY - 2013/6/27

Y1 - 2013/6/27

N2 - The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using invitro and invivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function.

AB - The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using invitro and invivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function.

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U2 - 10.1016/j.molcel.2013.04.012

DO - 10.1016/j.molcel.2013.04.012

M3 - Journal articles

C2 - 23685073

AN - SCOPUS:84880807019

SN - 1097-2765

VL - 50

SP - 831

EP - 843

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy

Abstract

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