TY - JOUR
T1 - Neuronal loss in Pelizaeus - Merzbacher disease differs in various mutations of the proteolipid protein 1
AU - Pierson, Christopher R.
AU - Woltjer, Randall L.
AU - Hobson, Grace M.
AU - Golden, Jeffrey A.
AU - Kupsky, William J.
AU - Schauer, Galen M.
AU - Bird, Thomas D.
AU - Skoff, Robert P.
AU - Sima, Anders A.F.
AU - Garbern, James Y.
N1 - Funding Information:
Acknowledgments The authors are especially grateful to the families who generously donated specimens for research. J.G. thanks the PMD Foundation, the National Institutes of Health (NS043783), the Children’s Research Center of Michigan, and the National Multiple Sclerosis Society (RG3204) for support. G.M.H. acknowledges the Nemours Foundation and National Institutes of Health grant P20 RR-020173-01 from the National Center for Research Resources. The authors also are grateful to the Alzheimer disease Research Center of the University of Washington for assistance.
PY - 2009
Y1 - 2009
N2 - Mutations affecting proteolipid protein 1 (PLP1), the major protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus - Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss. Although length-dependent axonal degeneration has been described in PLP1 null mutations, there have been no reports on neuronal degeneration in PMD patients. We now demonstrate widespread neuronal loss in PMD. The patterns of neuronal loss appear to be dependent on the mutation type, suggesting selective vulnerability of neuronal populations that depends on the nature of the PLP1 disturbance. Nigral neurons, which were not affected in patients with either null or severe misfolding mutations, and thalamic neurons appear particularly vulnerable in PLP1 duplication and deletion patients, while hippocampal neuronal loss was prominent in a patient with complete PLP1 gene deletion. All subjects showed cerebellar neuronal loss. The patterns of neuronal involvement may explain some clinical findings, such as ataxia, being more prominent in PMD than in other leukodystrophies. While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology.
AB - Mutations affecting proteolipid protein 1 (PLP1), the major protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus - Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss. Although length-dependent axonal degeneration has been described in PLP1 null mutations, there have been no reports on neuronal degeneration in PMD patients. We now demonstrate widespread neuronal loss in PMD. The patterns of neuronal loss appear to be dependent on the mutation type, suggesting selective vulnerability of neuronal populations that depends on the nature of the PLP1 disturbance. Nigral neurons, which were not affected in patients with either null or severe misfolding mutations, and thalamic neurons appear particularly vulnerable in PLP1 duplication and deletion patients, while hippocampal neuronal loss was prominent in a patient with complete PLP1 gene deletion. All subjects showed cerebellar neuronal loss. The patterns of neuronal involvement may explain some clinical findings, such as ataxia, being more prominent in PMD than in other leukodystrophies. While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology.
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U2 - 10.1007/s00401-009-0562-8
DO - 10.1007/s00401-009-0562-8
M3 - Article
C2 - 19562355
AN - SCOPUS:69949177941
SN - 0001-6322
VL - 118
SP - 531
EP - 539
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -