Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by the presence of glial cytoplasmic inclusions (GCIs) containing aggregated α‐synuclein (α‐Syn). Accurate diagnosis and monitoring of MSA present significant challenges, which can lead to potential misdiagnosis and inappropriate treatment. Biomarkers play a crucial role in improving the accuracy of MSA diagnosis, and phosphorylated α‐synuclein (p‐syn) has emerged as a promising biomarker for aiding in diagnosis and disease monitoring.

A literature search was conducted on PubMed, Scopus, and Google Scholar using specific keywords and MeSH terms without imposing a time limit. Inclusion criteria comprised various study designs including experimental studies, case‐control studies, and cohort studies published only in English, while conference abstracts and unpublished sources were excluded.

Increased levels of p‐syn have been observed in various samples from MSA patients, such as red blood cells, cerebrospinal fluid, oral mucosal cells, skin, and colon biopsies, highlighting their diagnostic potential. The α‐Syn RT‐QuIC assay has shown sensitivity in diagnosing MSA and tracking its progression. Meta‐analyses and multicenter investigations have confirmed the diagnostic value of p‐syn in cerebrospinal fluid, demonstrating high specificity and sensitivity in distinguishing MSA from other neurodegenerative diseases. Moreover, combining p‐syn with other biomarkers has further improved the diagnostic accuracy of MSA.

The p‐syn stands out as a promising biomarker for MSA. It is found in oligodendrocytes and shows a correlation with disease severity and progression. However, further research and validation studies are necessary to establish p‐syn as a reliable biomarker for MSA. If proven, p‐syn could significantly contribute to early diagnosis, disease monitoring, and assessing treatment response.