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PubMed This is a summary of 22 peer-reviewed journal articles Updated
Neurology

What Causes Alpha-Synuclein Clumping in MSA?

At a Glance

Alpha-synuclein clumping in MSA is a sporadic biological process driven by cellular waste disposal failures, neuroinflammation, and mitochondrial dysfunction in the brain's support cells. It is not caused by lifestyle choices, is not contagious, and is rarely hereditary.

In this answer

5 sections

01

A “Chain Reaction” of Misfolding

02

Cellular Stress and Waste Disposal

03

The Role of Inflammation

04

Are There Genetic or Environmental Triggers?

05

Looking Forward: How This Guides Research

When you are diagnosed with Multiple System Atrophy (MSA), it is completely normal to wonder, “Did I do something to cause this?” The clear and direct answer is no. The clumping of alpha-synuclein proteins in your brain was not caused by your diet, your exercise habits, or your lifestyle choices [1]. The exact “spark” that triggers this process remains unknown, but scientists are making significant progress in understanding the complex biological factors involved [2][3].

Here is what researchers currently understand about why these proteins misfold and gather in the brain, and how this knowledge is guiding the search for treatments.

A “Chain Reaction” of Misfolding

In MSA, a normal protein called alpha-synuclein loses its natural shape and becomes misfolded. Once one of these proteins misfolds, it acts like a template or “seed.” It bumps into other normal alpha-synuclein proteins and causes them to misfold too [4][5]. This creates a chain reaction, leading the misfolded proteins to clump together and spread through different parts of the brain [6][7].

Note: Researchers sometimes describe this spreading as a “prion-like” process. It is incredibly important to know that this refers only to how the protein behaves inside your brain. MSA is not contagious. You cannot pass it to your family, friends, or caregivers [4].

Unlike Parkinson’s disease, where clumps mostly form in nerve cells (neurons), in MSA, these clumps gather primarily in oligodendrocytes [4][8]. Oligodendrocytes are the brain’s support cells that produce myelin, the protective coating around nerve fibers. When alpha-synuclein clumps form in these support cells, they are called glial cytoplasmic inclusions (GCIs) [9][10]. The buildup of GCIs ultimately damages both the support cells and the neurons they protect [11][12].

Cellular Stress and Waste Disposal

Why do oligodendrocytes allow these clumps to form? Research points to issues within the cells themselves:

  • Faulty Waste Disposal (Autophagy): Cells have a built-in recycling system called autophagy to clear out old or damaged proteins. In MSA, this system seems to slow down or malfunction in oligodendrocytes, allowing the misfolded alpha-synuclein to build up instead of being cleared away [9][10].
  • Mitochondrial Dysfunction: The energy factories of the cells, called mitochondria, may not work properly. This leads to oxidative stress—a buildup of harmful molecules known as free radicals that damage the cell and create an environment where proteins are more likely to misfold [13][14].

The Role of Inflammation

Neuroinflammation (inflammation in the brain) plays a major role in the progression of MSA. When the alpha-synuclein proteins begin to clump in the oligodendrocytes, the brain’s immune system detects a problem [15][9].
This activates microglia, the brain’s immune cells. While these cells try to help, their chronic activation releases inflammatory chemicals (like cytokines) that inadvertently cause more damage and drive the disease forward [16][17].

Are There Genetic or Environmental Triggers?

Scientists believe MSA may result from a complex interaction of subtle environmental exposures and possibly minor genetic susceptibilities, though the exact “spark” remains a mystery. MSA is largely a sporadic disease (meaning it occurs randomly).

  • Genetics: Unlike some forms of Parkinson’s disease, there is no single “MSA gene” that causes the disease or is passed down to children [18][19]. While researchers are studying complex genetic variations that might make someone slightly more susceptible, MSA is rarely inherited [20][21].
  • Environmental Factors: There is growing evidence that long-term, cumulative exposure to certain environmental toxins might increase the risk of developing MSA [22]. Recent studies have found that people in certain occupational categories—particularly those with long-term exposure to organic solvents or heavy agricultural pesticides—may have a slightly higher risk if they are already genetically susceptible [22].

It is vital not to blame yourself or your career choices. Millions of people are exposed to these same environments without ever developing MSA. These factors are simply correlations being studied, not guaranteed causes.

Looking Forward: How This Guides Research

You did not cause your MSA [1]. The misfolding of alpha-synuclein is a complex biological event driven by cellular waste disposal failures and neuroinflammation.

While learning about this biology can be overwhelming, it is exactly this understanding that is paving the way for future therapies. Researchers are currently using this knowledge of inflammation, protein clumping, and cellular waste disposal to design new clinical trials aimed at slowing or stopping the progression of the disease [14][13].

Common questions in this guide

Is multiple system atrophy caused by my lifestyle choices?
No, MSA is not caused by your diet, exercise habits, or past lifestyle choices. The exact trigger is unknown, and it is incredibly important not to blame yourself for developing the disease.
Is multiple system atrophy contagious?
No, MSA is not contagious. While researchers sometimes describe the protein misfolding as a "prion-like" spreading process inside the brain, you cannot pass the disease to your family, friends, or caregivers.
Is multiple system atrophy hereditary?
MSA is considered a sporadic disease, meaning it occurs randomly and is rarely inherited. There is no single "MSA gene" that causes the condition or is passed down to children.
What are glial cytoplasmic inclusions in MSA?
Glial cytoplasmic inclusions (GCIs) are clumps of misfolded alpha-synuclein proteins that gather in oligodendrocytes, the brain's support cells. The buildup of these clumps damages both the support cells and the neurons they protect.
Can environmental factors cause multiple system atrophy?
Long-term exposure to certain toxins, like organic solvents or agricultural pesticides, may slightly increase the risk of developing MSA in genetically susceptible individuals. However, these are just potential risk factors, as millions of people have similar exposures without developing MSA.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Given what we know about alpha-synuclein and neuroinflammation, are there any clinical trials targeting these mechanisms that I might be eligible for?
  2. 2.Should I consider joining an MSA patient registry to help researchers understand the environmental and genetic factors better?
  3. 3.How does the fact that the clumps are in my support cells (oligodendrocytes) rather than neurons affect my symptom management and treatment plan?
  4. 4.Is there any value in undergoing genetic testing, or does the sporadic nature of MSA make it unnecessary for my family and me?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

Related questions

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References

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This page explains the biology of Multiple System Atrophy for educational purposes only and does not replace professional medical advice. Always consult your neurologist regarding your specific condition and medical history.

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