Rare Variants in Lysosomal Genes Linked to Parkinson’s, Study Finds

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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PD GENEration

Scientists have discovered a series of rare variants in genes that control the function of lysosomes — cell compartments responsible for digesting and recycling different types of molecules — that are associated with Parkinson’s disease.

The findings were published in an article, “Rare Variants in Specific Lysosomal Genes Are Associated with Parkinson’s Disease,” in the journal Movement Disorders.

Parkinson’s disease is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — along with brain inflammation. Although its specific causes are still not fully understood, scientists believe that genetic factors are important contributors to the onset of the disease.

Previous genome-wide association studies have identified several genetic variants associated with Parkinson’s. However, these variants explained only about 23% of the disease’s heritability pattern.

Mutations in the glucocerebrosidase (GBA) gene are a known risk factor for Parkinson’s development. GBA is a lysosomal gene that provides instructions to make the enzyme beta-glucocerebrosidase that is responsible for breaking down a fatty substance called glucocerebroside inside lysosomes.

Defects in protein degradation inside lysosomes, particularly alpha-synuclein, and in the recycling of certain cell compartments, such as energy-producing mitochondria, have been implicated in the development and progression of Parkinson’s.

Several studies have suggested that lysosomal malfunction can promote or potentiate the development of Parkinson’s. “Hence, there is good reason to hypothesize that rare variants in genes related to lysosomal function represent [Parkinson’s disease] risk factors as well,” the researchers wrote.

To explore in more detail the possible association between rare variants of lysosomal genes and Parkinson’s, a team of German researchers sequenced the coding regions (those that give rise to proteins) of 23 lysosomal gene candidates in 4,096 patients (mean average age of 67 years) with sporadic Parkinson’s,  and 4,096 individuals (mean age of 61 years) who did not have the disease (controls).

Using next‐generation sequencing, a powerful DNA-sequencing method, the investigators identified 1,256 rare genetic variants whose frequency among patients and controls was under 1%. From these, 898 were considered non-synonymous, 275 were synonymous, and 65 were either stop-gain or stop-loss variants.

Synonymous variants are those that, despite changing the DNA sequence of a gene, do not change the sequence of the protein they encode; in contrast, non-synonymous variants change both the DNA sequence of the gene and that of the protein they encode. Stop-loss and stop-gain variants are those in which alterations to the DNA sequence of a gene lead to the shortening or expansion of the protein they encode, respectively.

Analyses confirmed that rare variants found in the coding region of the GBA gene were positively associated with Parkinson’s. In addition, the investigators found that rare variants in other lysosomal genes, including ATP13A2, LAMP1, TMEM175, and VPS13C, were also associated with Parkinson’s.

However, they did not find a link between rare variants in the SMPD1 gene and Parkinson’s, which had previously been reported in another study.

Although researchers acknowledged that they likely “missed an unkown number of rare variants” due to certain limitations in their methodology, their findings demonstrated that “rare variants in selected lysosomal genes, first and foremost GBA, are associated with [Parkinson’s disease].”