TMEM106B C-Terminal fragment aggregation exacerbates α-synuclein and TDP-43 proteinopathy phenotypes.

Abstract

Genetic variation in the human gene encoding the lysosomal transmembrane protein 106B (TMEM106B) drives risk of neurodegenerative dementia. A C-terminal fragment of TMEM106B (TMEM CT) accumulates in lesions across neurodegenerative disease, potentially contributing to neurotoxicity and hampering efficacy of therapeutic interventions. Previously, we developed the first transgenic organism model of TMEM CT neuronal aggregation in Caenorhabditis elegans (C. elegans). We demonstrated that TMEM CT neuronal aggregation drives severe neuronal dysfunction and neuronal loss. To investigate the potential synergistic interaction of TMEM CT aggregation with other types of aggregated neurotoxic proteinopathies occurring in dementia, we assessed neuronal degeneration and pathogenic protein accumulation in bigenic C. elegans expressing TMEM CT and other key proteinopathies of neurodegeneration including a-synuclein, tau, and TAR DNA binding protein 43 (TDP-43). Our results showed strong neurotoxic synergy of TMEM106B with TDP-43 or -synuclein. However, we detected only mild synergy between TMEM106B and tau. This work provides evidence in support of TMEM CT aggregation as a significant participant in the neurodegenerative process attributed to other toxic protein aggregates. The work also highlights the importance of considering secondary proteinopathy contributions including TMEM CT aggregation when developing interventions against primary TDP-43 or -synuclein proteinopathies.