Neuronal α-synuclein toxicity is the key driver of neurodegeneration in multiple system atrophy.

Multiple system atrophy (MSA) is a rare, rapidly progressing neurodegenerative disorder often misdiagnosed as Parkinson's disease (PD). Although both conditions share some clinical features, MSA is distinct in its pathological hallmark: oligodendroglial cytoplasmic α-synuclein (α-Syn) inclusions, known as glial cytoplasmic inclusions. These glial cytoplasmic inclusions are pathognomonic for MSA, but they do not lead to significant oligodendroglial cell loss. Instead, MSA is characterized by a substantially greater loss of non-dopaminergic neurons in the nigrostriatal and olivopontocerebellar systems compared with PD. This widespread neuronal degeneration, which is not seen to the same extent in PD, plays a crucial role in the clinical presentation of MSA and is important to consider if PD is to be redefined as a neuronal α-Syn disease. It also raises the question of differences in the potential toxicity of lesions in MSA and the underlying cause of neuronal death in MSA. By combining an N-terminus α-Syn antibody that reveals more α-Syn pathology and super-resolution microscopy, we identified α-Syn fibrils in MSA neurons penetrating the nucleus from the cytoplasm, leading to nuclear destruction and neuronal death. Our data indicate an early invasion of neuronal nuclei by α-Syn pathology in MSA, precipitating rapid nuclear envelope destruction, as observed through significant structural damage, including the loss of Lamin integrity. Although the progression of α-Syn pathology from the cytoplasm to the nucleus might be similar in oligodendroglia and neurons, the aggregation state of the α-Syn proteoforms involved differs because proteolytic resistance of α-Syn inclusions is significantly higher in neurons, and the nucleus is destroyed. We describe the progressive impact of α-Syn nuclear pathology on MSA neurons and show that this is a more detrimental and rapid pathology driving neurodegeneration. Our data suggest that oligodendroglial inclusions contain more soluble, less toxic α-Syn proteoforms, consistent with two distinct α-Syn filaments in MSA. We propose renaming MSA as a neuronal nuclear and oligodendroglial α-synucleinopathy to reflect these two distinct pathologies better.