A single genetic variation can increase your risk sixfold.
Imagine a disease that strikes with the tremors of Parkinson's, the imbalance of cerebellar damage, and the disabling dizziness of autonomic failure—all at once. This is multiple system atrophy (MSA), a rare but devastating neurodegenerative disorder that progresses rapidly and currently has no cure.
For decades, MSA was considered purely sporadic, appearing randomly without warning. But groundbreaking genetic research has uncovered a different story—one where subtle variations in our DNA can dramatically increase susceptibility to this cruel disease. At the heart of this discovery lies the SNCA gene, which provides the blueprint for alpha-synuclein, a protein that becomes dangerously misfolded in the brains of MSA patients.
Typically leads to severe disability within 5-6 years
Alpha-synuclein accumulates in oligodendrocytes
Multiple system atrophy is a progressive neurodegenerative disorder characterized by a combination of autonomic nervous system failure (leading to dizziness, urinary problems, and sexual dysfunction), parkinsonism (stiffness, slowness, and tremors), and cerebellar dysfunction (problems with balance and coordination) 5 .
The disease is classified into two main subtypes:
Geographical differences exist in subtype prevalence, with MSA-P more common in European and North American populations, while MSA-C occurs more frequently in East Asian countries like Japan 5 .
MSA is considered the most aggressive synucleinopathy, typically leading to severe disability within 5-6 years and death within an average of 10 years from symptom onset . What makes MSA particularly distinctive pathologically is the predominant accumulation of misfolded alpha-synuclein protein in oligodendrocytes—the support cells that produce the myelin sheath insulating nerve fibers—rather than primarily in neurons as seen in other similar diseases .
The SNCA gene, located on human chromosome 4q22.1, encodes the alpha-synuclein protein 2 6 . While its precise normal functions are not fully understood, research suggests it plays important roles in regulating neurotransmitter release, synaptic function, and the plasticity of dopaminergic neurons 2 .
The gene gained notoriety when it was discovered that alpha-synuclein represents the major component of Lewy bodies—the abnormal protein aggregates found in Parkinson's disease brains 2 4 . This connection to neurodegeneration was further strengthened when mutations and multiplications of the SNCA gene were identified in rare familial forms of Parkinson's disease 2 4 .
In MSA, the relationship is slightly different. Rather than mutations in the protein-coding sequence, research has focused on single nucleotide polymorphisms (SNPs)—single letter changes in the DNA sequence—that appear to modify disease risk without necessarily altering the protein structure 1 6 .
The team began with 384 single nucleotide polymorphisms (SNPs) that had shown the strongest association with Parkinson's disease in their previous genome-wide association study.
These 384 SNPs were genotyped in an initial cohort of 413 MSA cases and 3,974 healthy controls. After rigorous quality control checks, 339 SNPs were analyzed for association with MSA.
The 10 most significantly associated SNPs from the screening phase were then genotyped in an independent replication cohort of 108 MSA cases and 537 controls to verify the findings.
The researchers applied strict statistical corrections for multiple testing to ensure that any associations identified were unlikely to occur by chance alone.
The findings were striking. Two specific SNPs—rs11931074 and rs3857059—located in and near the SNCA gene showed highly significant associations with MSA risk in both the screening and replication cohorts 1 .
| SNP ID | Location | Risk Allele | Combined Odds Ratio | Statistical Significance |
|---|---|---|---|---|
| rs11931074 | Downstream of SNCA | T | 6.2 | p = 5.5 × 10−12 |
| rs3857059 | SNCA Intron 4 | G | 5.9 | p = 2.1 × 10−10 |
The odds ratios of approximately 6.0 for homozygous risk allele carriers indicated that individuals with two copies of the risk variant had more than six times the odds of developing MSA compared to those with one or no copies 1 . This represents one of the strongest genetic risk effects ever identified in neurodegenerative diseases.
| SNP ID | Screening Stage p-value | Replication Stage p-value | Combined Analysis p-value |
|---|---|---|---|
| rs11931074 | 1.7 × 10−7 | 1.6 × 10−4 | 5.5 × 10−12 |
| rs3857059 | 6.9 × 10−4 | 1.3 × 10−6 | 2.1 × 10−10 |
The study also revealed that the recessive model provided the best fit for the data, meaning that both copies of the gene needed to carry the risk variant for the effect to be substantial 1 . The two significant SNPs were found to be in complete linkage disequilibrium (r² = 1.0), meaning they were inherited together as a block in the population studied 1 .
| Research Tool | Function in MSA Research |
|---|---|
| GoldenGate Assays | Genotyping platform used to determine the genetic variants present in DNA samples 1 |
| Polymerase Chain Reaction (PCR) | Technique to amplify specific DNA segments for further analysis 1 |
| SNaPshot Method | Multiplex platform for genotyping single nucleotide polymorphisms 1 |
| PLINK Software | Statistical toolset for analyzing genome-wide association data 1 |
| Snca-GFP Knock-In Mice | Mouse models with fluorescently tagged alpha-synuclein to track protein localization and dynamics 3 |
| Alpha-Synuclein Preformed Fibrils (PFFs) | Laboratory-generated protein aggregates used to seed and study synuclein pathology 3 |
While the association between SNCA variants and MSA risk is well-established, the story is more complex than it initially appears:
The strong association between specific SNCA variants and MSA observed in European populations has proven difficult to replicate in Asian cohorts 6 . This may be partly explained by differences in the frequency of risk alleles across populations. For instance, the frequency of the rs11931074 "T" risk allele is considerably higher in Asian populations (51-58%) than in European populations (2-10%) 6 .
How do these non-coding SNCA variants actually influence disease risk? Researchers propose several mechanisms:
The discovery of SNCA's role in MSA has far-reaching implications beyond simply understanding disease cause. These genetic insights are driving advances in several key areas:
Genetic testing for SNCA variants may eventually help clinicians distinguish MSA from other similar conditions earlier in the disease course, when interventions might be most effective.
Understanding how SNCA variants increase risk opens doors to targeted therapies aimed at reducing alpha-synuclein expression, preventing abnormal protein aggregation, and enhancing clearance of misfolded proteins .
As we better understand how different genetic profiles influence disease presentation and progression, we move closer to tailoring treatments to individual patients' genetic makeup.
The discovery that SNCA variants dramatically increase MSA risk has transformed our understanding of this devastating disease. What was once considered purely sporadic is now recognized as having important genetic components that interact with environmental and other factors to determine disease susceptibility.
While much work remains to fully unravel how these genetic variations lead to the distinctive pathology of MSA, each finding brings us closer to effective treatments. The sixfold increased risk associated with specific SNCA variants represents both a sobering reality for those who carry them and a powerful clue for researchers determined to crack MSA's code.
As genetic research continues to advance, hope grows that we will eventually transform these scientific discoveries into therapies that can slow, halt, or even prevent the progression of multiple system atrophy.
To learn more about multiple system atrophy or support research, consider connecting with organizations such as the Multiple System Atrophy Coalition or the Movement Disorder Society.