The Unfolded Protein Response
: A potential link between heterozygous mutations in GBA1 and Lewy body dementia?

Student thesis: Doctoral ThesisDoctor of Philosophy


Lewy body dementia (LBD) is characterised by the deposition of a-synuclein containing Lewy bodies throughout cortical brain regions. Pathology is confounded by the co-occurrence of pathological Ab and tau deposition. LBD comprises dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), distinguished by the timing of onset of classical symptoms: cognitive impairment occurs at least one year prior to motor impairment in DLB and vice versa in PDD. Currently, there are no disease modifying therapeutic agents for LBD.
Heterozygous mutations in GBA1 have become established as the most common genetic risk factor for Parkinson’s disease and dementia with Lewy bodies. GBA1 encodes the lysosomal enzyme glucocerebrosidase. Deficient glucocerebrosidase activity causes accumulation of a-synuclein. Homozygous GBA1 mutation causes the lysosomal storage disorder Gaucher’s disease. In this thesis, a possible mechanism underlying the link between GBA1 mutation and LBD is investigated - the unfolded protein response (UPR). We hypothesise that the UPR is activated in response to mutant GBA1 but is unable to serve a protective function under increasing levels of stress. We also characterise the impact of heterozygous GBA1 mutation (D427V) on mice to establish whether a cognitive impairment phenotype is displayed which may be translational for the study of LBD.
The results presented in this thesis support the activation of both IRE1a and PERK mediated UPR responses since we show increased expression of spliced XBP1 and CHOP in a L444P mutant GBA1 SH-SY5Y cell model. We also demonstrate spliced XBP1 ceases to be expressed under increasing cellular stress whilst CHOP expression continues. Since CHOP is associated with detrimental cell outcomes, predominantly initiation of apoptosis, we suggest that the imbalance of UPR responses towards CHOP mediated effects may potentially underlie pathological consequences associated with GBA1 mutation. Results presented in this thesis also reveal a previously unreported progressive cognitive decline in D427V/WT GBA1 mice.
In conclusion, preventing the withdrawal of protective spliced XBP1 mediated effects and continued expression CHOP may be a therapeutic avenue for further investigation in D427V/WT GBA1 mice which show promising signs of being a translational model for LBD.
Date of Award2018
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMartin Broadstock (Supervisor) & Paul Francis (Supervisor)

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