Purkinje cell fusion and binucleate heterokaryon formation in multiple sclerosis cerebellum

A major conceptual consideration in both endogenous and therapeutic central nervous system repair is how damaged (or senescent) neurons, given their often enormously complex and extensive network of connections, can possibly be replaced. The recent observation of fusion of circulating bone marrow cells with, in particular, cerebellar Purkinje cells, as well as the subsequent formation of stable heterokaryons, offers a tantalizing potential solution to this difficulty. Here, we have explored Purkinje cell fusion and heterokaryon formation in the human brain and the influence of central nervous system inflammation. We analysed post-mortem cerebellum tissue from patients who had multiple sclerosis and from appropriate controls. Purkinje cells were analysed for heterokaryon formation using immunohistochemistry techniques and chromosome composition using fluorescence in situ hybridization. For the first time in humans we show a disease-related increase in Purkinje cell fusion and heterokaryon formation. We have shown that heterokaryon formation takes place in control subjects, and that the frequency of this event is considerably increased in patients with multiple sclerosis, the prototypical inflammatory brain disease, with ∼0.4% of Purkinje cells being binucleate heterokaryons. No mononucleate polyploid Purkinje cell heterokaryons were found. The observation that heterokaryon formation in the cerebellum occurs as part of the central nervous system inflammatory reaction suggests a potential mechanism of neural repair. It also suggests an exciting new avenue for therapeutic intervention, as enhancement or manipulation of fusion events may have a therapeutic role in cellular protection in multiple sclerosis.