Fig. 2.

Potential mechanisms for tau and TDP-43 synergy in AD. There are numerous pathways that potentially underlie tau and TDP-43 synergistic neurotoxicity. These include interactions within the nucleus during regulated transport between the nucleus and cytoplasm, or associations with DNA, RNA, or nuclear speckles. In the cytoplasm, alterations in microtubule dynamics, stability, or transport along microtubules, derangement of cellular signaling including post-translational modifications such as phosphorylation, ubiqitination, acetylation, or SUMOylation, or formation of stress granules could lead to phenotypic enhancement of tau and TDP-43. Finally, misfolded tau or TDP-43 protein can impair normal cellular proteostasis mechanisms, which may have a broader impact on other aggregation prone proteins