C9orf72 -FTD/ALS pathogenesis: evidence from human neuropathological studies

AbstractWhat are the most important and treatable pathogenic mechanisms inC9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage theC9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominentC9orf72-associated features, such as TDP-43 loss-of-function, TDP-43 aggregation, and nuclear transport defects. Finally, we review potential disease-modifying epigenetic and genetic factors and the natural history of the disease across the lifespan. Throughout, we emphasize the importance of anatomical precision when studying how candidate mechanisms relate to neuronal, regional, and behavioral findings. We further highlight methodological approaches that may help address lingering knowledge gaps and uncertainties, as well as other logical next steps for the field. We conclude that anatomically oriented human neuropathological studies have a critical role to play in guiding this fast-moving field toward effective new therapies.

Source: Acta Neuropathologica - October 27, 2018 Category: Neurology Source Type: research