The E3 ubiquitin ligase protein, cyclin F (encoded by CCNF) has a role in substrate recognition for protein degradation within the ubiquitin proteasomal system. Mutations in this gene have recently been linked to the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia. To investigate the role of CCNF dysfunction in neurodegenerative disease, we aimed to develop novel transgenic zebrafish models that constitutively overexpress CCNF fusion proteins. After several attempts at establishing these transgenic lines, with side-by-side successful controls, it became apparent that generation of constitutively overexpressing CCNF fusion transgenic lines was not feasible. This failure appears to be a result of toxicity associated with persistent overexpression of CCNF fusion proteins in the developing embryo that precludes germ-line transmission of the transgene. The observations from our study indicate that an additional screening stage of zebrafish embryos, and/or the use of a temporal inducible system/mechanism is warranted in studies that aim to develop transgenic models expressing potentially toxic proteins, to circumvent the issues produced by expression during early developmental stages.