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Glucocerebrosidase Mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease

Lookup NU author(s): Dr Marzena Kurzawa-Akanbi, Dr Peter Hanson, Professor Peter Blain CBE, Debbie Lett, Professor Ian McKeith, Professor Patrick Chinnery, Dr Christopher Morris

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Abstract

ABSTRACT: Lewy body disease (LBD) development is enhanced by mutations in the GBA gene coding for glucocerebrosidase (GCase). The mechanism of this association is thought to involve an abnormal lysosomal system and we therefore sought to evaluate if lysosomal changes contribute to the pathogenesis of idiopathic LBD. Analysis of post-mortem frontal cortex tissue from 7 GBA mutation carriers with LBD, 5 GBA mutation carriers with no signs of neurological disease and human neural stem cells exposed to a GCase inhibitor was used to determine how GBA mutation contributes to LBD. GBA mutation carriers demonstrated a significantly reduced level of GCase protein and enzyme activity and retention of glucocerebrosidase isoforms within the endoplasmic reticulum (ER). This was associated with enhanced expression of the lysosomal markers LAMP1 and LAMP2, though the expression of ATP13A2 and Cathepsin D was reduced, along with the decreased activity of Cathepsin D. The ER unfolded protein response (UPR) regulator BiP/GRP78 was reduced by GBA mutation and this was a general phenomenon in LBD. Despite elevation of GRP94 in LBD, individuals with GBA mutations showed reduced GRP94 expression, suggesting an inadequate UPR. Finally, human neural stem cell cultures showed that inhibition of GCase causes acute reduction of BiP, indicating that the UPR is affected by reduced glucocerebrosidase activity. The results indicate that mutation in GBA leads to additional lysosomal abnormalities, enhanced by an impaired UPR, potentially causing α-synuclein accumulation.


Publication metadata

Author(s): Kurzawa-Akanbi M, Hanson PS, Blain PG, Lett DJ, McKeith IG, Chinnery PF, Morris CM

Publication type: Article

Publication status: Published

Journal: Journal of Neurochemistry

Year: 2012

Volume: 123

Issue: 2

Pages: 298-309

Print publication date: 22/08/2012

ISSN (print): 0022-3042

ISSN (electronic): 1471-4159

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1111/j.1471-4159.2012.07879.x

DOI: 10.1111/j.1471-4159.2012.07879.x

PubMed id: 22803570


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