Figure 7

Proposed pathogenic mechanisms in TDP-43-mediated neurodegneration converge onto disruption of protein and RNA homeostasis. Proteins involved in protein and RNA homeostasis are labeled as grey and green, respectively. (Upper panel) Normal functions of ALS/FTD-linked proteins. 1) Three ALS-linked genes (VCP, p62 and CHMP2B) are required for proper turnover of TDP-43, which is degraded both by the proteasome and by autophagy. 2) TDP-43 regulates the expression of the same ALS-linked genes that are required for its own degradation as well as 3) a key autophagy induction protein, ATG7. TDP-43 also regulates two other RNA-binding proteins linked to ALS (FUS/TLS and Ataxin-2). TDP-43, FUS/TLS and Ataxin-2 form RNA-protein granules that are degraded through 4) autophagy/granulophagy. Thus, TDP-43 governs both protein and RNA homeostasis and 5) its own level is tightly maintained. (Lower panel) Disrupted protein and RNA homeostasis that fuels a feed-forward loop driving disease progression. An initiating event that triggers disease initiation can occur at multiple points in either protein or RNA homeostasis pathways, including genetic mutations that predispose one pathway to be more error-prone or other non-genetic factors, such as aging. The well-documented 1) decline in proteostasis during aging may lead to elevated accumulation of TDP-43. Subsequently, 2) the genes that are controlled by TDP-43 become de-regulated, including 3) loss of expression of ATG7, which in turn reduces 4) autophagy (and granulophagy). The net result of this produces 5) disrupted autoregulation of TDP-43 with an increased cytoplasmic concentration of TDP-43, which provokes 6) prion-like templating of it followed by propagation and spread. These gain-of-toxic properties induce over-production of “nonfunctional prion-like” TDP-43 that leads to further loss of TDP-43 function. Similar scenarios could operate for prion-like domain-containing RNA binding proteins, such as FUS/TLS and hnRNP A2/B1.