Researchers Link PD Risk to Lysosomal Gene Mutations

A team of neurodegenerative disease researchers has suggested that multiple genetic defects may act in combination to degrade lysosomal function, which enhances Parkinson’s disease (PD) susceptibility.

Based on previous evidence indicating that mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, were also potent risk factors for Parkinson’s disease, investigators at Baylor College of Medicine (Houston, TX, USA) examined whether a genetic burden of variants in other lysosomal storage disorder genes was more broadly associated with Parkinson’s disease susceptibility.


Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins, or mucopolysaccharides.

The lysosome is commonly referred to as the cell's recycling center because it processes unwanted material into substances that the cell can utilize. Lysosomes break down this unwanted matter via enzymes. Lysosomal disorders are usually triggered when a particular enzyme exists in too small an amount or is missing altogether. When this happens, excess products destined for breakdown and recycling are stored in the cell. Lysosomal storage diseases affect mostly children and they often die at a young and unpredictable age, many within a few months or years of birth. Many other children die of this disease following years of suffering from various symptoms of their particular disorder.

The investigators used the sequence kernel association test to interrogate variant burden among 54 lysosomal storage disorder genes. The Sequence Kernel Association Test (SKAT) is a tool for region based testing of rare variants from sequencing data. In particular, the SKAT was designed for testing the association of rare variants from sequence data with a dichotomous or quantitative trait. This approach was followed by the leveraging of whole exome sequencing data from 1156 Parkinson’s disease cases and 1679 control subjects.

Results published in the November 13, 2017, online edition of the journal Brain revealed that there was a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson’s disease risk. The majority of Parkinson’s disease cases (56%) had at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carried multiple alleles.

"We studied the largest Parkinson's disease genetic dataset currently available and found that, although each of the damaging mutations within these genes is individually uncommon, they are common as a group within the Parkinson's cohort," said senior author Dr. Joshua Shulman, assistant professor of neurology, neuroscience, and molecular and human genetics at Baylor College of Medicine.

"Although more research remains to be done, these data suggest the interesting possibility that damage to the lysosome might be at the core of Parkinson's disease. It might be possible that Parkinson's disease and lysosomal storage disorders have similar fundamental biological mechanisms."

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