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 (cell with a large number of nuclei), offers a tantalizing potential solution to this difficulty. This study explored Purkinje cell fusion and heterokaryon formation in the human brain and the influence of central nervous system inflammation. The investigators’ analysed post-mortem cerebellum tissue from MSers and from appropriate controls. Purkinje cells were analysed for heterokaryon formation using immunohistochemistry techniques and chromosome composition using fluorescence in situ hybridization or FISH.
“FISH is a technique used to paint chromosomes so that you can count them or the number of a particular gene in a cell.”
FISH – painted chromosome. Are they not beautiful?
For the first time in humans this study shows 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 MSers, the prototypical inflammatory brain disease, with ∼0.4% of Purkinje cells being binucleate heterokaryons (two nuclei). 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 MS.
Types of neuroaxonal degeneration.
“What is happening here is that cells that are derived from the blood migrate across the blood-brain-barrier, possibly stem cells, and fuse with CNS cells. Heterokaryon is big name to describe an increased number of nuclei and chromosomes. Why do cells need additional chromosomes? It assumed that cells with increased synthetic requirements need more active genes to make enough proteins for the cells survival and functioning; doubling the number of a particular gene from 2 to 4 doubles the potential transcriptional activity of that cell, i.e. the synthesis of messenger RNA that the cell uses to make proteins. This is not surprising when you see how large, and long, nerve cells are. This paper suggests that this is manifestation of repair, however, there is no data that shows this. You have to realise the CNS is very different to other organs in that it is wired in a very complex manner. This is why I am sceptical about fixing or restoring CNS function once a pathway has been damaged; not only do we have to replace lost cells, but we have to coax them into rewiring the pathway that has been lost. Unfortunately, there is another problem called post-synaptic degeneration, which is the loss or death of downstream neurones when upstream neurons die (figure b in the cartoon above). This why we need to focus on the reality of the here and now and try prevent damage in MS before it happens. Fixing damage after the nerve cells and their processes have died is going to be very difficult. task.”