FIGURE 2.

Proposed model for the regional heterogeneity of TDP-43 C-terminal fragments (CTFs). CTFs may accumulate in the brains of people with ALS and FTLD-TDP due to elevated activity of proteases such as caspases and calpains, genetic predisposition, or upregulation of alternative TARDBP transcripts that produce a truncated protein. The lack of CTFs in the ALS spinal cord may arise from mechanisms including enhanced CTF clearance by chaperone-mediated autophagy or the ubiquitin-proteasome system (UPS).