GCase Mutations Prevent Clearing of Toxic Clumps, Treatment Possible

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Mutations in the enzyme glucocerebrosidase (GCase) prevent it from entering the lysosome — a cell’s recycling center — where it clears away unwanted materials such as alpha-synuclein toxic clumps that cause Parkinson’s disease and ultimately kill nerve cells, a recent study found.

These encouraging findings may help to validate efforts to repurpose medications approved for other disorders to treat Parkinson’s, Cure Parkinson’s reported on a webpage. Treatment repurposing is a goal of the U.K. nonprofit’s International Linked Clinical Trials program, and a Phase 2 trial found that an existing medication called ambroxol might protect neurons against alpha-synuclein clumps via its effects on GCase activity.

Ambroxol, a type of respiratory medicine, has been shown to increase GCase activity and improve how lysosomes work. It’s also been shown to prevent the death of cells with mutations in GBA — the gene providing the instructions to make GCase.

The study, “Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy,” was published in Science Advances by an international team of researchers led by David Sulzer, PhD.

Sulzer is a professor of psychiatry, neurology, and pharmacology at Columbia University, and he sits on the International Linked Clinical Trials committee.

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The lysosome contains enzymes that break down materials that are no longer needed into building blocks that can be reused and built upon by cells.

Alpha-synuclein can be broken down within the lysosome via a process called chaperone-mediated autophagy. For this to occur, the alpha-synuclein protein must be recognized by a special type of molecule called a chaperone. Among other roles, a chaperone prevents proteins from clumping together and helps deliver them to the lysosome for disposal. (Autophagy is a natural process used by cells to degrade damaged or unwanted components.)

GCase is also transported to the lysosome, where it breaks down two types of fatty molecules — glucosylceramide and glucosylsphingomyelin.

Mutations in this enzyme are linked to an increased risk of developing Parkinson’s, and up to 20% of Parkinson’s patients have one copy of a mutated GBA gene.

Researchers found that GCase mutations make the enzyme stick with a chaperone to the outside of the lysosome, blocking other proteins from getting inside and being broken down via autophagy.

The researchers first tracked down the enzyme inside cells with either a healthy (wild-type) or a mutated version of GCase. They found that the wild-type version was present at higher levels within lysosomes than the mutated version.

They next confirmed this finding in the brains of mice and post-mortem brain tissue from idiopathic (of unknown cause) Parkinson’s patients and people without this disease as a control group. Samples came from 12 patients without GBA mutations, 13 patients with one copy (heterozygous) of a mutated GBA gene, and seven age-matched controls.

“We found … that only subjects heterozygous for [mutated] GCase exhibited GCase on the [outside] of lysosomes, where we also detected high levels of established CMA [chaperone-mediated autophagy] substrates, including [alpha]-synuclein,” the researchers wrote.

The scientists then turned their attention to the specific portion of GCase (called a motif) needed for the enzyme to enter the lysosome. They already knew that a special motif of five protein building blocks, known as a pentapeptide motif, is needed for chaperone recognition.

“We found that half of the GCase in lysosomes from postmortem human GBA-PD [Parkinson’s disease] brains was present on the lysosomal surface and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy,” the researchers wrote.

Importantly, the team found that in the presence of alpha-synuclein, the mutated GCase caused nerve cells to die, but its wild-type version didn’t.

“This cell death was dependent on the presence of the CMA motif in GCase, indicating that the toxic interaction was dependent on [mutated] GCase inhibition of CMA,” they wrote.

In a Phase 2 clinical trial co-sponsored by Cure Parkinson’s (NCT02941822), ambroxol was found to reach the brain of patients with idiopathic Parkinson’s and safely increase GCase levels while reducing alpha-synuclein accumulation there. Scientists are planning a larger Phase 3 clinical trial to determine if ambroxol can slow the disease’s progression, the group stated on its webpage.