In vivo approach to myelin turnover and oligodendrocyte-dependent axonal integrity

Abstract

Deletion of the most abundant protein of CNS myelin, proteolipid protein (PLP) causes type 2 spastic paraplegia (SPG2) in humans, which is characterized by axonal degeneration. The assumption that the primary cause of SPG2 is the lack of PLP from oligodendrocytes has been challenged by studies reporting Plp gene products (official gene name Plp1) also in a subset of neurons. To clarify the cellular origin of SPG2, we established mice with a floxed Plp allele to selectively delete Plp in neurons or oligodendrocytes. Recombination of Plp in excitatory projection neurons did not cause neuropathology, whereas oligodendroglial deletion of Plp caused the complete neurodegenerative spectrum observed in Plpnull/Y mice including axonopathy, gliosis and elevated numbers of T cells in the brain and thus provide a novel model of SPG2. We conclude that the primary cause of SPG2 is the lack of PLP in oligodendrocytes. To better understand the interplay of PLP-deficient oligodendrocytes, axons and T cells, we analyzed the emergence of neuropathological events upon Plp-deletion over time in tamoxifen-inducible Plp knockout mice. Importantly, axonal spheroids were observed prior to elevated numbers of T cells, implying that axonopathy occurs independent from T cells in this model, at least initially. Together, by analyzing novel mouse models of SPG2 this work provides relevant information about the cellular neuropathology caused by PLP-deficiency.