Oligodendrocytes Prune Axons Containing α-Synuclein Aggregates In Vivo: Lewy Neurites as Precursors of Glial Cytoplasmic Inclusions in Multiple System Atrophy?

alpha-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by alpha-Synuclein (alpha-Syn) fibrils. In Parkinson's disease (PD) and dementia with Lewy bodies, intraneuronal alpha-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites in the neuronal processes. In multiple system atrophy (MSA) alpha-Syn aggregates are also found within mature oligodendrocytes (OLs) where they form Glial Cytoplasmic Inclusions (GCIs). However, the origin of GCIs remains enigmatic: (i) mature OLs do not express alpha-Syn, precluding the seeding and the buildup of inclusions and (ii) the artificial overexpression of alpha-Syn in OLs of transgenic mice results in a burden of soluble phosphorylated alpha-Syn but fails to form alpha-Syn fibrils. In contrast, mass spectrometry of alpha-Syn fibrillar aggregates from MSA patients points to the neuronal origin of the proteins intimately associated with the fibrils within the GCIs. This suggests that GCIs are preassembled in neurons and only secondarily incorporated into OLs. Interestingly, we recently isolated a synthetic human alpha-Syn fibril strain (1B fibrils) capable of seeding a type of neuronal inclusion observed early and specifically during MSA. Our goal was thus to investigate whether the neuronal alpha-Syn pathology seeded by 1B fibrils could eventually be transmitted to OLs to form GCIs in vivo. After confirming that mature OLs did not express alpha-Syn to detectable levels in the adult mouse brain, a series of mice received unilateral intra-striatal injections of 1B fibrils. The resulting alpha-Syn pathology was visualized using phospho-S129 alpha-Syn immunoreactivity (pSyn). We found that even though 1B fibrils were injected unilaterally, many pSyn-positive neuronal somas were present in layer V of the contralateral perirhinal cortex after 6 weeks. This suggested a fast retrograde spread of the pathology along the axons of crossing cortico-striatal neurons. We thus scrutinized the posterior limb of the anterior commissure, i.e., the myelinated interhemispheric tract containing the axons of these neurons: we indeed observed numerous pSyn-positive linear Lewy Neurites oriented parallel to the commissural axis, corresponding to axonal segments filled with aggregated alpha-Syn, with no obvious signs of OL alpha-Syn pathology at this stage. After 6 months however, the commissural Lewy neurites were no longer parallel but fragmented, curled up, sometimes squeezed in-between two consecutive OLs in interfascicular strands, or even engulfed inside OL perikarya, thus forming GCIs. We conclude that the 1B fibril strain can rapidly induce an alpha-Syn pathology typical of MSA in mice, in which the appearance of GCIs results from the pruning of diseased axonal segments containing aggregated alpha-Syn.

Automated summary

alpha-Synucleinopathies are neurodegenerative disorders characterized by the accumulation of insoluble alpha-Synuclein fibrils. These fibrils can form Lewy bodies in somata and Lewy neurites in neuronal processes. In multiple system atrophy, alpha-Synuclein aggregates are found in mature oligodendrocytes, but the origin of these aggregates is still unknown.