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.
Highlights
IntroductionThe presence of glucocerebrosidase in Lewy bodies and Lewy neurites in patients carrying Glucocerebrosidase gene (GBA) mutations suggests that glucocerebrosidase can contribute to the aggregation of a-synuclein and Lewy body formation (Goker-Alpan et al 2010)
Previous studies in several populations have demonstrated the association between Glucocerebrosidase gene (GBA) mutations and Lewy body disease (Sidransky et al 2009)
The results of this study indicate that GBA heterozygotes show reduced activities of glucocerebrosidase enzyme in the frontal cortex tissue irrespective of disease state, consistent with previous reports (Choi et al 2011; Mazzulli et al 2011)
Summary
The presence of glucocerebrosidase in Lewy bodies and Lewy neurites in patients carrying GBA mutations suggests that glucocerebrosidase can contribute to the aggregation of a-synuclein and Lewy body formation (Goker-Alpan et al 2010). Increased a-synuclein immunoreactivity has been observed in cells treated with conduritol B epoxide (CBE), an inhibitor of GCase activity, along with accumulation of a-synuclein within the substantia nigra in CBE-treated mice (Manning-Bog et al 2009) This indicates that reduced glucocerebrosidase activity may promote alterations in a-synuclein biology and these changes are present in the brains of mice and in neuronal cells carrying GBA mutations (Cullen et al 2011; Mazzulli et al 2011; Sardi et al 2011).
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