Research: LKCMedicine Researchers Find Rare Protein-Altering Variants in Genes That Significantly Increase the Risk of Parkinson’s Disease

By Sanjay Devaraja, Editor, LKCMedicine's Redefine Newsletter

A team consisting of researchers from LKCMedicine have identified SMPD1 as a new Parkinson’s disease gene. Their findings show that carrying one functionally defective copy of SMPD1 will result in a more than two-fold increased risk of Parkinson’s disease. This suggests that restoration of SMPD1 deficiency could be a viable interception point and therapeutic strategy for Parkinson’s disease. 

Such a concept is currently under trial for Niemann-Pick disease (i.e. homozygous loss of SMPD1). Furthermore, the discovery of rare variants which substantially increase disease risk in Asian populations will allow risk prediction and population screening for high-risk individuals for early monitoring and participation in neuroprotection trials.

Parkinson’s disease is a lifelong and progressive neurodegenerative movement disorder, affecting more than 10 million people worldwide. It is increasing in incidence globally as a result of the ageing population. Despite decades of research, the cause is unknown, and treatment remains symptomatic, with levodopa being the cornerstone medication of choice. There is thus a pressing need for new therapeutic approaches.

The exome (or the ~1% of the genome that encodes for protein) has a special place in precision medicine. This is because coding-sequence mutations affect individual predisposition to disease by directly altering protein function. When linked to human diseases, the unique property of protein-altering genetic variants often facilitates advances in their treatment by uncovering new drug targets.

Most of such exome sequencing studies have been done in European-ancestry populations. The Asian population is the largest in the world and has the greatest potential for novel genetic discoveries especially in the study of rare genetic variants.

Multicentre collaborative partnership generated a new East Asian whole exome sequencing dataset of 4,298 persons with Parkinson’s disease and 5,512 unaffected controls from Singapore, Malaysia, Hong Kong, South Korea, and Taiwan. The top findings were validated in a further 5,585 persons with Parkinson’s disease and 5,642 controls from 3 independently ascertained collections of Asian and European ancestry.

A team consisting of LKCMedicine researchers identified rare protein-altering variants in GBA1 and SMPD1 that are significantly associated with increased risk of Parkinson’s disease. While this is the first study to confirm SMPD1 as a bona fide Parkinson’s disease gene, GBA1 is a well-established Parkinson’s disease risk gene. SMPD1 encodes for acid sphingomyelinase, an enzyme responsible for breaking down sphingomyelin to ceramide and phosphorylcholine. It is important for the function of lysosomes, which are small compartments in human cells that digest and recycle excess or wanted substances within the cell.

Individuals who carry two defective copies of either GBA1 or SMPD1 have a severe, autosomal recessive, childhood-onset lysosomal storage disease, Gaucher’s disease or Niemann-Pick disease, respectively. While individuals who carry just one defective copy do not show signs of lysosomal storage disease, they are at increased risk of Parkinson’s disease.

Researchers designed biological assays and tested the functional readouts for each of the 125 protein-altering genetic variants at SMPD1 that emerged from sequence analysis of 21,037 participants. The spectrum of acid sphingomyelinase enzymatic activity for these 125 variants ranged from normal activity to severe impairment (< 20% of normal activity). Individuals who carry any SMPD1 variant with ≤44 percent of normal enzymatic activity had a ~2.24-fold increased risk of Parkinson’s disease.

About one percent of the East Asian population carries a particular genetic variant p.Pro332Arg variant (with 70% reduction of enzymatic activity); and slightly more carry other rare SMPD1 or GBA1 variants. Although these variants are individually rare, they more than double an individual’s risk of developing Parkinson’s disease. Such carriers can be identified for early monitoring and intervention to lower their risk of developing the disease.