Mutations in Genes Other Than GBA May Collectively Raise Parkinson’s Risk and Severity, Study Suggests

Mutations in the SNCA and CTSB genes — among the many known to increase the likelihood of Parkinson’s disease — also contribute to the risk associated with mutations in the GBA gene, one of this disease’s most common and significant genetic risk factors, a study shows.

Its results further suggest an interaction between the CTSB and GBA genes, and that raising the levels of the protein the CTSB gene is responsible for producing — cathepsin B — may be a way of treating Parkinson’s.

The study, “Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia,” is available on the bioRxiv pre-print server.

The GBA gene contains the instructions to produce the enzyme glucocerebrosidase (GCase) that is active in lysosomes, special compartments within cells that break down and recycle different types of molecules.

GBA mutations, which reduce GCase activity, are one of the most common genetic risk factors for Parkinson’s and dementia with Lewy bodies (LBD), found in 3%–20% of patients in different populations. GBA mutations confer a risk of these diseases that 1.4 times to more than 10 times higher.

Parkinson’s patients with GBA mutations also have earlier ages at onset and faster disease progression, previous studies found.

Researchers hypothesize that the loss of GCase activity leads to a reduced ability to degrade alpha-synuclein, the protein produced through instructions in the SNCA gene. Mutations in the SNCA gene are associated with a greater risk of Parkinson’s disease, likely due to increased alpha-synuclein levels.

A buildup of abnormal alpha-synuclein can result in toxic aggregates of insoluble small fibers that deposit in the form of Lewy bodies, hallmarks of Parkinson’s and LBD.

Despite the well-established link between GBA mutations and Parkinson’s, most people carrying these mutations will not develop the disease, implying the influence of other genetic and/or environmental factors on GBA-associated risk.

An international team of researchers set out to evaluate genetic factors weighing on GBA-associated risk, including those that influence the age at which the disease develops.

They analyzed genetic data covering 217,165 people, stored in several large databases using genome wide association studies (GWAS) and the most recent Parkinson’s-associated genetic risk score.

GWAS scan complete sets of DNA, or genomes, of large numbers of people to identify all the genetic changes associated with a disease or trait of interest, and the various weights in terms of disease or trait risk they are assigned. This data is then used to generate genetic risk scores to determine someone’s predisposition to a given disease or trait.

Out of a genetic analysis of 22,757 Parkinson’s patients, 13,431 people whose parents have Parkinson’s, 622 LBD patients, and 180,355 unaffected individuals, the team identified 1,772 Parkinson’s patients, 711 Parkinson’s relatives, and 7,624 unaffected people with GBA mutations.

Results also showed that the GBA-associated risk of developing Parkinson’s disease was significantly influenced by the presence of mutations in the SNCA and CTSB genes. CTSB contains the instructions to produce cathepsin B, an enzyme suggested to be involved in the degradation of alpha-synuclein in lysosomes.

Nerve cells derived from people with GBA mutations had significantly lower cathepsin B levels than those derived from people without such mutations, suggesting a link between GBA and cathepsin B.

In other words, the combination of GBA mutations and mutations in the SNCA and/or CTSB genes may result in greater lysosomal function impairment and a greater buildup of protein aggregates in nerve cells, resulting in an increased risk of Parkinson’s disease.

Age at Parkinson’s onset in patients with GBA mutations was significantly lower than in patients without them, with an average onset at almost 56.81 vs. 60.54 years old.  Mutations in SNCA and TMEM175 — a gene involved in lysosomal processes and associated with increased risk of Parkinson’s and lower age of onset — were also found to potentially affect the age of onset of GBA-associated Parkinson’s.

“These data provide a genetic basis for modification of GBA-associated [Parkinson’s disease] risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease,” the researchers wrote.

These results “have important implications for selection of GBA carriers for therapeutic interventions,” and suggest that “cathepsin B might play a larger role in [Parkinson’s disease] than previously thought and that increasing CTSB/cathepsin B levels could be a potential therapeutic strategy,” they added.

The team emphasized, however, that larger GWAS (studies with greater numbers of people carrying GBA mutations) and more extensive studies into genetic factors are needed to confirm these results.