TMEM106B C‐terminal fragments aggregate and drive neurodegenerative proteinopathy in transgenic Caenorhabditis <i>elegans</i>

Pan-neuronal expression of human TMEM106B C-terminal fragments (TMEM CT) in C. elegans neurons drives a suite of disease-related phenotypes useful for modeling the molecular and cellular features of TMEM106B neuropathology. TMEM CT expression results in extensive TMEM aggregation and accumulation of highly detergent insoluble protein species. TMEM CT expression causes moderate to severe neuronal dysfunction dependent on TMEM CT abundance as measured by stereotypical behavioral readouts. TMEM CT expression drives significant neurodegenerative changes. Dendra2 tagged TMEM exhibits similar properties to untagged TMEM allowing ready visualization of the protein. TMEM CT aggregates accumulate adjacent to but not within lysosomes. PGRN loss of function does not impact TMEM CT toxicity. Modifiers of tau and TDP-43 proteinopathies have little impact on TMEM CT-related neurodegenerative phenotypes.