Glucocerebrosidase deficiency in dopaminergic neurons induces microglial activation without neurodegeneration

Human Molecular Genetics
Federico N SoriaPierre-Olivier Fernagut

Abstract

Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation whereas elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remain elusive, partially because of lack of aged models of GBA1 deficiency. As knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons. DAT-Cre and GBA1-floxed mice were bred to obtain selective homozygous disruption of GBA1 in midbrain dopamine neurons (DAT-GBA1-KO). Mice were followed for motor function, neuronal survival, alpha-synuclein phosphorylation and glial activation. Susceptibility to nigral viral vector-mediated overexpression of mutated (A53T) alpha-synuclein was assessed. Despite loss of GBA1 and substrate accumulation, DAT-GBA1-KO mice displayed normal motor performances and preserved dopaminergic neurons despite robust microglial a...Continue Reading

References

Jan 1, 1990·Methods in Enzymology·B Storrie, E A Madden
Nov 27, 1999·The Journal of Biological Chemistry·H PyoI Jou
Feb 16, 2002·Methods : a Companion to Methods in Enzymology·K J Livak, T D Schmittgen
Jan 20, 2004·Molecular Genetics and Metabolism·Alicia LwinEllen Sidransky
Jul 6, 2004·Molecular Genetics and Metabolism·Kondi WongRaphael Schiffmann
Oct 22, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sheila M FlemingMarie-Françoise Chesselet
Nov 2, 2004·Movement Disorders : Official Journal of the Movement Disorder Society·Christine SatoEkaterina Rogaeva
Sep 7, 2006·Proceedings of the National Academy of Sciences of the United States of America·Ida Berglin EnquistStefan Karlsson
Oct 24, 2007·Proceedings of the National Academy of Sciences of the United States of America·Ida Berglin EnquistStefan Karlsson
May 13, 2009·Archives of Neurology·Lorraine N ClarkKaren Marder
Oct 23, 2009·The New England Journal of Medicine·E SidranskyS G Ziegler
Sep 15, 2010·Acta Neuropathologica·Ozlem Goker-AlpanEllen Sidransky
May 31, 2011·Molecular Genetics and Metabolism·Laura ParkkinenAndrew J Lees
May 9, 2012·Brain : a Journal of Neurology·Einat B VitnerAnthony H Futerman
Jul 25, 2012·Proceedings of the National Academy of Sciences of the United States of America·Chiara Di MaltaAndrea Ballabio
Oct 5, 2012·Annals of Neurology·Matthew E GeggAnthony H V Schapira
Oct 20, 2012·Lancet Neurology·Ellen Sidransky, Grisel Lopez
Feb 7, 2013·Frontiers in Cellular Neuroscience·Audrey KarperienHerbert F Jelinek
Apr 13, 2013·Movement Disorders : Official Journal of the Movement Disorder Society·Benjamin DehayErwan Bezard
Apr 17, 2013·JAMA Neurology·Michael A NallsEllen Sidransky
Jan 31, 2014·Brain : a Journal of Neurology·Karen E MurphyGlenda M Halliday
Sep 14, 2014·Nature Medicine·Lior MayoFrancisco J Quintana
Mar 25, 2015·Molecular and Cellular Neurosciences·Anthony H V Schapira
Jun 23, 2015·Movement Disorders : Official Journal of the Movement Disorder Society·Matthew E GeggAnthony H V Schapira
Jun 29, 2015·Brain : a Journal of Neurology·Roy N AlcalayXiaokui Zhang
Jul 25, 2015·Acta Neuropathologica Communications·Mathieu BourdenxBenjamin Dehay
Aug 11, 2015·Frontiers in Aging Neuroscience·Rommy von BernhardiJaime Eugenín
Aug 13, 2015·ELife·Vikram AgarwalDavid P Bartel
Nov 26, 2015·Current Opinion in Pharmacology·Stephanie M Matt, Rodney W Johnson

❮ Previous
Next ❯

Citations

Feb 1, 2018·The FEBS Journal·Matthew E Gegg, Anthony H V Schapira
Nov 2, 2018·Science Translational Medicine·Richard GordonTrent M Woodruff
Jan 23, 2020·Journal of Neurochemistry·Marco ToffoliAnthony H V Schapira
May 7, 2020·Frontiers in Aging Neuroscience·Micol AvenaliSilvia Cerri
Nov 22, 2020·Movement Disorders : Official Journal of the Movement Disorder Society·Patricia García-SanzRosario Moratalla
Apr 3, 2021·Brain Communications·Azucena Perez-CanamasStephen M Strittmatter

❮ Previous
Next ❯

Related Concepts

Related Feeds

Amygdala and Midbrain Dopamine

The midbrain dopamine system is widely studied for its involvement in emotional and motivational behavior. Some of these neurons receive information from the amygdala and project throughout the cortex. When the circuit and transmission of dopamine is disrupted symptoms may present. Here is the latest research on the amygdala and midbrain dopamine.

Cell-Type Specific Viral Vectors

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.

Basal Ganglia

Basal Ganglia are a group of subcortical nuclei in the brain associated with control of voluntary motor movements, procedural and habit learning, emotion, and cognition. Here is the latest research.

Cell-Type-Specific Viral Vectors (ASM)

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.

Alpha-Synuclein Aggregation (MDS)

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.

Cell-Type-Specific Viral Vectors

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.