Investigation of oligodendroglial pathology in amyotrophic lateral sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease. TDP-43 is found in pathological protein aggregates in neurons and glia in ALS and it is part of some mRNA transport granules. MBP messenger RNA (mRNA) must be transported to the oligodendrocyte processes for correct myelination. If TDP-43 were part of MBP mRNA transport granules, its aggregation could lead to loss of MBP in the CNS. Additionally, C9orf72 is a gene whose GGGGCC expansion mutation causes ALS. The expansion binds hnRNP-A2, a protein essential for the transport of MBP mRNA. This interaction may lead to the sequestration of hnRNP-A2, reducing its availability and causing a shortage of MBP in the CNS.
Aims: To characterise the oligodendroglial pathology and the loss of MBP in our cohort of ALS cases, and to create zebrafish lines to investigate the development of oligodendroglial degeneration in sporadic ALS and C9orf72 ALS. The overarching hypothesis of the project is that the observed oligodendrocyte degeneration in ALS is primarily caused by a dysfunction of MBP mRNA transport, causing demyelination.
Methods & Results: Using immunohistochemistry in human post mortem tissue, this project reports a greater, distinct ubiquitin-related glial pathology in the primary motor cortex of C9orf72-ALS cases. This C9orf72-related glial pathology was independent of the dipeptide-repeat protein inclusions usually found in the motor neurones of these patients. Using Western blot and qPCR, the levels of MBP and PLP, another myelin protein that is translated in the oligodendrocyte cell body, were measured. A reduction in the levels of MBP, but not those of PLP, was found in the spinal cord lateral corticospinal tracts of ALS cases, which was more pronounced in C9orf72 ALS. This reduction of the MBP levels was not accompanied by either a reduction in the number of axons panning that area or the levels of MBP mRNA.
Conclusions: These results suggest that an impairment of mRNA transport is the main cause of the reduced MBP levels in the spinal cord of ALS patients and that oligodendrocyte degeneration precedes axonal degeneration in ALS. Were this confirmed using in vivo models of ALS, it would imply that ALS begins as a myelinopathy which later causes the apparition of neuronal pathology and death. None of the in vivo models trialled in this project were successful, but others have created promising models that will surely help understand oligodendroglial degeneration in ALS.