SPG2 HSP mechanism described

Posted - December 2017 in Research Highlights

Loss of specialised support cells the cause


Mutations in the PLP1 gene associated with HSP have been found in this study to cause the loss of specialised cells called oligodendrocytes that normally function to support and protect the neurons, leading to progressive degeneration of the long axons of neurons.


. . .



Proteolipid protein (PLP) is the most abundant integral membrane protein in compact central nervous system myelin, and null mutations of the PLP1 gene cause spastic paraplegia type 2 (SPG2). SPG2 patients and PLP-deficient mice exhibit only moderate abnormalities of myelin but progressive degeneration of long axons. Since PLP1 gene products are detected in a subset of neurons it has been suggested that the loss of neuronal PLP1 expression could be the cause of the axonal pathology. To test this hypothesis, we created mice with a floxed PLP1 allele for selective Cre-mediated recombination in neurons.


We find that recombination of PLP1 in excitatory projection neurons does not cause neuropathology, whereas oligodendroglial targeting of PLP1 is sufficient to cause the entire neurodegenerative spectrum of SPG2 including axonopathy and secondary neuroinflammation.


We conclude that PLP-dependent loss of oligodendroglial support is the primary cause of axonal degeneration in SPG2.


SOURCE: Glia. 2017 Nov;65(11):1762-1776. doi: 10.1002/glia.23193. Epub 2017 Aug 24. PMID: 28836307


Genetic dissection of oligodendroglial and neuronal PLP1 function in a novel mouse model of spastic paraplegia type 2.


Lüders KA1, Patzig J1, Simons M2, Nave KA1, Werner HB1.


1 Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, 37075, Germany.

2 Cellular Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, 37075, Germany.



Add your comment on this story