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Acta Neuropathologica

, Volume 137, Issue 1, pp 1–26 | Cite as

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

  • Sarat C. Vatsavayai
  • Alissa L. Nana
  • Jennifer S. Yokoyama
  • William W. SeeleyEmail author
Review

Abstract

What are the most important and treatable pathogenic mechanisms in C9orf72-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 the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominent C9orf72-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.

Keywords

C9orf72 Frontotemporal dementia (FTD) Amyotrophic lateral sclerosis (ALS) Dipeptide repeat proteins RNA foci TAR DNA binding protein of 43 kDa (TDP-43) 

Notes

Acknowledgements

We thank our colleagues at the UCSF Memory and Aging Center for conversations related to this manuscript and the UCSF study participants for their contributions to neurodegeneration research. This work was supported by NIH grants AG023501, AG019724, AG033017, The Bluefield Project to Cure FTD, and the Tau Consortium.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Sarat C. Vatsavayai
    • 1
  • Alissa L. Nana
    • 1
  • Jennifer S. Yokoyama
    • 1
  • William W. Seeley
    • 1
    • 2
    Email author
  1. 1.Memory and Aging Center, Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of PathologyUniversity of California, San FranciscoSan FranciscoUSA

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