Single-nucleus RNA-seq of striatal tissue from MSA, PD, and controls shows PD microglia with MHC-II–linked proinflammatory signatures and more homeostatic astrocytes, whereas MSA features microglia in an immune-tolerant/exhausted state, reactive astrocytes, compromised oligodendrocyte signaling,…

By defining divergent microglial activation versus exhaustion and linking CSF-driven phagocytic deficits to MSA, the study highlights immune-modulatory and phagocytosis-enhancing interventions and CSF-based biomarkers as translational avenues relevant to synucleinopathy therapeutic discovery.

Multiple system atrophy (MSA) is a rare, age-related neurodegenerative disease that shares clinical and pathological features with Parkinson's disease (PD) but presents a more devastating disease course. To elucidate the distinct cellular pathophysiology, we performed single-nucleus RNA sequencing on postmortem striatal brain tissue from 7 MSA and 12 PD patients, and 10 non-neurological cases. Here, we show significant compositional differences in astroglia and microglia subtypes, while oligodendroglia and neurons are comparable. PD brains show abundant microglia expressing MHC class II HLA haplotypes, indicative of a proinflammatory state, alongside more homeostatic astrocytes. In contrast, MSA lack activated microglia but has more reactive astrocytes compared to PD. Transcriptomic analysis suggests compromised oligodendrocyte signaling in MSA, with microglia being in a state of immune tolerance or exhaustion. Microglia derived from iPSC exposed to patient cerebrospinal fluid exhibit reduced phagocytic activity, especially in MSA. These findings underscore a dysfunctional immune response in MSA as a potential contributor to the more severe pathophysiology of MSA.