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Annu Rev Pathol. 2018 Oct 24. doi: 10.1146/annurev-pathmechdis-012418-012955. [Epub ahead of print]

RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration.

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Department of Pathology, University of California, San Francisco, California 94143, USA; email:
Department of Neurology, University of California, San Francisco, California 94148, USA.
Pathology Service 113B, Veterans Affairs Medical Center, San Francisco, California 94121, USA.


Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights for the pathogenesis and potential therapeutic targets of FTLD. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see for revised estimates.

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