PUMA Protein May Underlie Oligodendroglial Cell Death in MS
A pro-apoptotic protein underlies oligodendroglial cell death in toxic demyelination and possibly in MS also
The PUMA protein (p53 upregulated modulator of apoptosis) underlies oligodendroglial cell death in an animal model of toxic demyelination and possibly in multiple sclerosis (MS) also, according to findings of a new study reported in Glia (Hagemeier et al., 2013).
“[MS] is a disease of the central nervous system characterized by demyelination, inflammation, gliosis, and axonal damage,” wrote Karin Hagemeier of the Institute of Neuropathology, University Hospital Münster in Germany, and colleagues. “Chronic MS lesions display a relative homogenous histological pattern with extensive demyelination and almost complete loss of oligodendrocytes, whereas initial lesion stages are more heterogeneous. One lesion pattern that accounts for approximately one third of early lesions is characterized by so-called fields of dying oligodendrocytes with apoptotic morphology, for example, condensed and pyknotic nuclei [features consistent with cell death].”
In MS and other human demyelinating diseases, death of oligodendroglial cells that form myelin results in the characteristic disruption of the myelin sheath surrounding nerve fibers, causing slowed nerve conduction and clinical symptoms. However, the mechanisms underlying oligodendroglial cell death in these diseases are only partly understood.
To study these mechanisms, the investigators used mice bred to be deficient in PUMA or Noxa (phorbol-12-myristate-13-acetate-induced protein 1; noxa is Latin for “damage”). They induced toxic demyelination by feeding the mice cuprizone, a chemical that chelates or binds copper atoms needed for myelin production. In this model, death of oligodendroglial cells required the BH3-only protein PUMA, but not Noxa protein.
Differentiation of primary oligodendrocytes in both of these mouse strains was similar to that in mice with normal expression of Noxa and PUMA. However, oligodendrocytes from PUMA-deficient mice were more resistant to cell death, whether it occurred spontaneously or in response to the toxins staurosporine or nitric oxide.
“PUMA-deficiency is sufficient to almost completely prevent oligodendroglial cell death, demyelination, and microglia activation in toxic demyelination, whereas Noxa is dispensable for oligodendroglial cell death in this animal model,” the study authors wrote.
PUMA Linked to Demyelination in Human Cells
Even more convincing, in terms of the possible significance of PUMA for MS pathophysiology, were findings from human cell lines and from MS lesions. Administering staurosporine to cause cell death in primary human oligodendrocytes resulted in increased levels of PUMA messenger RNA. In addition, oligodendrocytes in MS lesions had detectable levels of PUMA protein.
“PUMA is an important oligodendroglial cell death mediator that contributes to oligodendroglial cell death induced by different stimuli,” the study authors concluded. “Furthermore, PUMA is also expressed in oligodendrocytes in MS lesions, suggesting that PUMA not only plays an essential role for oligodendroglial cell death in the cuprizone model but potentially also in MS. Further experiments are required to determine the importance of PUMA for oligodendroglial cell death in human demyelinating diseases.”
Key open questions
- Will further research confirm and better define the importance of PUMA for oligodendroglial cell death in MS and other human demyelinating diseases?
- Would PUMA blockade be of potential value as a therapeutic target in MS and other human demyelinating diseases?
The German Research Foundation funded this study. The study authors did not report any financial disclosures.