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PubMed This is a summary of 14 peer-reviewed journal articles Updated
Neurology

The Biology of MSA-C and Misdiagnoses

At a Glance

Multiple System Atrophy, cerebellar type (MSA-C) is caused by misfolded alpha-synuclein proteins clumping in the brain's support cells. This damages the region controlling balance. Because it shares symptoms with other conditions, it is frequently misdiagnosed as Parkinson's or other ataxias.

To understand Multiple System Atrophy, Cerebellar type (MSA-C), it is helpful to look past the symptoms and into the microscopic world of the brain. While it shares some outward similarities with Parkinson’s disease and other balance disorders, its biological “blueprint” is unique [1].

The Core Culprit: Alpha-Synuclein “Strains”

At the heart of MSA-C is a protein called alpha-synuclein [1]. In a healthy brain, this protein is soluble and moves freely. However, in MSA, it misfolds into a “toxic” shape.

Crucially, researchers have discovered that the alpha-synuclein in MSA is a different strain (a specific structural fold) than the one found in Parkinson’s disease [2]. This MSA strain is more aggressive and has a “prion-like” ability to spread, causing other healthy proteins to misfold and clump together in a chain reaction [3][4].

What are Glial Cytoplasmic Inclusions (GCIs)?

The most defining biological feature of MSA is where these protein clumps end up. In Parkinson’s, they usually form “Lewy bodies” inside neurons (nerve cells). In MSA, they form Glial Cytoplasmic Inclusions (GCIs) primarily inside oligodendrocytes [1][5].

Oligodendrocytes are not nerve cells themselves; they are “support cells” that create myelin, the protective insulation around your nerves. When GCIs build up, they damage these support cells, causing the insulation to break down and interfering with the brain’s ability to send signals [6]. This process is what leads to the shrinking (atrophy) of specific brain regions.

MSA-C vs. MSA-P: A Tale of Two Regions

While both types of MSA involve the same GCI pathology, they damage different “neighborhoods” in the brain:

  • MSA-C (Cerebellar type): The damage is concentrated in the olivopontocerebellar system (the brainstem and cerebellum) [1]. This area controls balance, which is why ataxia is the primary symptom [7].
  • MSA-P (Parkinsonian type): The damage is focused on the striatonigral pathway. This area controls movement speed and fluidity, leading to stiffness and tremors similar to Parkinson’s [1].

Distinguishing MSA-C from “Look-Alikes”

Because ataxia is a common symptom, MSA-C is frequently confused with other conditions. Doctors use specific “biomarkers” and clinical rules to tell them apart:

Condition Biological/Diagnostic Differentiator
Spinocerebellar Ataxias (SCAs) These are usually genetic (inherited). MSA-C is sporadic (not inherited). SCAs rarely show the “hot cross bun” sign on MRI that is common in MSA-C [8][9].
CANVAS Caused by a specific mutation in the RFC1 gene. It often includes a chronic cough and sensory loss, which are rare in MSA-C [10].
SAOA (Sporadic Adult-Onset Ataxia) A “catch-all” term for ataxia with no known cause. The main difference is that SAOA patients do not have the severe autonomic failure (bladder/blood pressure issues) required for an MSA diagnosis [11][12].
Parkinson’s Disease Involves different protein folds and different cell types (neurons). Autonomic failure in Parkinson’s is usually much milder and occurs much later than in MSA-C [13][14].

Understanding these biological differences is vital because it confirms that your symptoms are the result of a specific, identifiable disease process—not just “old age” or a more common condition like Parkinson’s [1].

Common questions in this guide

How is the alpha-synuclein in MSA-C different from Parkinson's disease?
In MSA-C, the alpha-synuclein protein folds into a different, more aggressive shape than in Parkinson's disease. It also primarily forms clumps inside the brain's support cells, called oligodendrocytes, rather than inside the nerve cells themselves.
What are Glial Cytoplasmic Inclusions (GCIs)?
GCIs are clumps of misfolded alpha-synuclein protein that build up inside oligodendrocytes. This buildup damages these vital support cells, causing the protective insulation around your nerves to break down and disrupting brain signals.
What is the difference between MSA-C and MSA-P?
Both types involve the same harmful protein clumps, but they damage different areas of the brain. MSA-C affects the olivopontocerebellar system, causing balance issues, while MSA-P affects the striatonigral pathway, causing stiffness and tremors similar to Parkinson's.
Why is MSA-C frequently misdiagnosed?
Because MSA-C shares common symptoms like ataxia (balance issues) with other disorders, it can be hard to identify at first. It is often confused with Parkinson's, spinocerebellar ataxias, or CANVAS until specific MRI signs or severe autonomic symptoms appear.
Do I need genetic testing if I have symptoms of MSA-C?
Since MSA-C is not an inherited condition, doctors may recommend genetic testing to rule out similar disorders that are genetic. For example, testing for the RFC1 gene can help confirm whether you have a genetic condition called CANVAS instead of MSA-C.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Did my MRI show signs of 'olivopontocerebellar atrophy' or specific markers like the 'hot cross bun' sign?
  2. 2.How does the 'strain' of alpha-synuclein in MSA differ from that in Parkinson’s, and how does that affect my prognosis?
  3. 3.Should I have genetic testing for the RFC1 gene to rule out CANVAS?
  4. 4.Are my autonomic symptoms severe enough to definitively distinguish this from Sporadic Adult-Onset Ataxia (SAOA)?
  5. 5.How does the involvement of oligodendrocytes, rather than just neurons, change the way you approach my treatment?

Questions For You

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References

References (14)
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    Chemical disaggregation of alpha-synuclein fibrils as a therapy for synucleinopathies.

    Wu S, Hernandez Villegas NC, Schekman R

    Proceedings of the National Academy of Sciences of the United States of America 2023; (120(11)):e2300965120 doi:10.1073/pnas.2300965120.

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    Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein.

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    Acta neuropathologica communications 2015; (3()):75 doi:10.1186/s40478-015-0254-7.

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    α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb.

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    PMID: 31888771
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    Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models.

    Mavroeidi P, Arvanitaki F, Karakitsou AK, et al.

    Acta neuropathologica 2019; (138(3)):415-441 doi:10.1007/s00401-019-02014-y.

    PMID: 31011860
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    Alpha synuclein-mediated cytoskeletal dysfunction impairs myelination in human oligodendrocytes.

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    Acta neuropathologica 2025; (150(1)):33 doi:10.1007/s00401-025-02933-z.

    PMID: 40973885
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    Voxel-Based Meta-Analysis of Gray Matter Abnormalities in Multiple System Atrophy.

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    Frontiers in aging neuroscience 2020; (12()):591666 doi:10.3389/fnagi.2020.591666.

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    Vertical pons hyperintensity and hot cross bun sign in cerebellar-type multiple system atrophy and spinocerebellar ataxia type 3.

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    Radiological hints for differentiation of cerebellar multiple system atrophy from spinocerebellar ataxia.

    Chen HC, Lee LH, Lirng JF, Soong BW

    Scientific reports 2022; (12(1)):10499 doi:10.1038/s41598-022-14531-0.

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    Screening for RFC-1 pathological expansion in late-onset ataxias: a contribution to the differential diagnosis.

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    Journal of neurology 2022; (269(10)):5431-5435 doi:10.1007/s00415-022-11192-x.

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    Can Autonomic Testing and Imaging Contribute to the Early Diagnosis of Multiple System Atrophy? A Systematic Review and Recommendations by the Movement Disorder Society Multiple System Atrophy Study Group.

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    Movement disorders clinical practice 2020; (7(7)):750-762 doi:10.1002/mdc3.13052.

    PMID: 33043073
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    Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy.

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    The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy.

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    PMID: 35445419

This page explains the biology and pathology of MSA-C for educational purposes only. Always consult a neurologist or movement disorder specialist for accurate diagnosis and interpretation of your specific symptoms.

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