GCase low in sporadic Parkinson's brains

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Matthew Gegg, Anthony Schapira and colleagues (UCL, with John Hardy and Nicholas Wood), Annals of Neurology 2012. Kathleen Murphy, Glenda Halliday and colleagues (Sydney, with Ellen Sidransky of the NIH), Brain 2014. Funders were not read.

What happened

GBA mutations are the commonest genetic risk factor (landmark 16), and GCase and synuclein feed each other (landmark 35). The question was whether GCase is low only in carriers.

• Gegg 2012. GCase activity was measured in five brain areas of Parkinson's brains with GBA mutations (9-14 brains) and sporadic Parkinson's brains (12-14). Carriers had lower activity in all but frontal cortex, worst in the substantia nigra (58% lower, p < 0.01). Sporadic brains also had lower activity in the substantia nigra (33% lower, p < 0.05) and cerebellum (24% lower, p < 0.05). GCase protein was low in both groups, and signs of an activated unfolded-protein stress response were seen. In cells, extra synuclein or PINK1 deficiency lowered GCase protein.
• Murphy 2014. Nineteen sporadic Parkinson's brains without GBA1 mutations versus 10 controls. GCase protein and activity were reduced early, in brain regions with raised synuclein and little pathology, linked to reduced chaperone-mediated autophagy (a recycling route) and lower ceramide.

The result has since been reproduced by independent groups. Chiasserini 2015 (PD 26, dementia with Lewy bodies 16, controls 13, screened for GBA mutations) found GCase down 23% in caudate and 12% in substantia nigra in PD. Moors 2019 (15 per group) found 21% lower activity in the substantia nigra of PD and DLB, and lower activity also in patients without GBA variants.

Why it moved us toward a cure

It widened the target. If GCase is low in most people with Parkinson's, a GCase-raising drug such as ambroxol (landmark 40) is not just a carrier treatment. It also set up the question of why GCase drops, which the LRRK2 link (landmark 197) partly addresses.

Outcome

Open. Autopsy tissue is small and cannot show cause and effect: low GCase could result from the disease, and the drops in sporadic brains are modest (12–33%) compared with 58% or ~40% in carriers. Venglustat and BIA 28-6156 have failed in GBA trials (landmark 69).

Sources

• Gegg et al., Ann Neurol 2012;72:455–463, DOI 10.1002/ana.23614
• Murphy et al., Brain 2014;137:834–848, DOI 10.1093/brain/awt367
• Chiasserini et al., Mol Neurodegener 2015;10:15, DOI 10.1186/s13024-015-0010-2
• Moors et al., Mol Neurobiol 2019;56:1344–1355, DOI 10.1007/s12035-018-1090-0
• Checked 19 Oct 2026: Europe PMC lists no erratum or retraction for Gegg 2012 or Murphy 2014 (Murphy 2014 has two commentaries). Neither paper lists Masliah as an author.
• Not yet verified: full texts; whether GCase activity changes track disease stage in living patients.