GCase and synuclein feed each other

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

Joseph Mazzulli and Dimitri Krainc (Massachusetts General Hospital, Harvard) with Ellen Sidransky (NHGRI, NIH), Gregory Grabowski (Cincinnati Children's) and Guy Caldwell (University of Alabama, worm work). Paid for by NIH grants (NINDS, NIDDK and intramural), per Europe PMC.

What happened

GBA mutations raise Parkinson's risk about fivefold (landmark 16). This paper asked why. Using neurons, including human iPSC-derived dopamine neurons (landmark 32), Gaucher mouse models (4L/PS-NA and D409H), a worm model and human brain tissue, the team found:

• Cutting GCase (glucocerebrosidase, the lysosome's fat-clearing enzyme) in neurons lowered breakdown of long-lived proteins by about 40% and raised alpha-synuclein about 1.8-fold, while tau did not change in primary neurons. The enzyme's fatty substrate (glucosylceramide) also built up about fourfold.
• That substrate stabilised soluble, toxic-prone synuclein oligomers (small clusters) in a test tube.
• In reverse, extra synuclein impaired the delivery of GCase to the lysosome. In Parkinson's cortex, GCase protein was about 40% lower (cingulate cortex) and lysosome-enriched activity about 50% lower. Human tissue numbers were small, for example 3 controls and 6 Parkinson's brains in one analysis.

Cell 146(1):37–52, 23 June 2011. A separate Annals of Neurology paper (Cullen et al., Ann Neurol 69:940–953, 2011, from Link Medicine and Genzyme) reported partly different results: short chemical inhibition of GCase did not raise synuclein, while some mutant GBA forms did.

Why it moved us toward a cure

It turned a genetic association into a mechanism and made a therapeutic prediction: raising lysosomal GCase might break the loop, even in people without GBA mutations. That reasoning underlies ambroxol (landmark 40) and the other GCase-targeted drugs.

Outcome

Open. The loop is supported by cell, worm, mouse and limited human data, mostly from one group. Alzforum commentators (Laura Parkkinen, Oxford, and others) noted that most Gaucher patients and carriers do not develop parkinsonism, and Cullen's lab saw no synuclein rise with short chemical inhibition, which its author put down to the shorter treatment. No correction or retraction was found; PubMed lists three comment notes. Trials of GBA-directed drugs have so far been mostly negative: venglustat (2023) and BIA 28-6156 (2026) failed, ambroxol is in Phase 3 (dead ends).

Sources

• Mazzulli et al., Cell 2011;146:37–52, DOI 10.1016/j.cell.2011.06.001 (PMC copy)
• Cullen et al., Ann Neurol 2011;69:940–953, DOI 10.1002/ana.22400
• Alzforum, "A Feedforward Loop Links Gaucher and Parkinson's Diseases?" (independent comments)
• ScienceDaily, MGH release, 24 Jun 2011
• Not yet verified: full author affiliations beyond those listed; replication of the "reverse arm" (synuclein blocking GCase delivery) by other labs; the worm data (supplement not read); PubPeer not checked.