Abstract
The RNA binding protein (RBP) RBM45 forms nuclear and cytoplasmic inclusions in neurons and glia in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), and Alzheimer's disease (AD). The normal functions of RBM45 are poorly understood, as are the mechanisms by which it forms inclusions in disease. To better understand the normal and pathological functions of RBM45, we evaluated whether the protein functions via association with several membraneless organelles and whether such an association could promote the formation of nuclear RBM45 inclusions. Under basal conditions, RBM45 is diffusely distributed throughout the nucleus and does not localize to membraneless organelles, including nuclear speckles, Cajal bodies, or nuclear gems. During cellular stress, however, nuclear RBM45 undergoes a reversible, RNA-binding dependent incorporation into nuclear stress bodies (NSBs). Chronic stress leads to the persistent association of RBM45 with NSBs and the irreversible accumulation of nuclear RBM45 inclusions. We also quantified the cell type- and disease-specific patterns of RBM45 pathology in ALS, FTLD-TDP, and AD. RBM45 nuclear and cytoplasmic inclusions are found in both neurons and glia in ALS, FTLD-TDP, and AD but are absent in non-neurologic disease controls. Across neurodegenerative diseases, RBM45 nuclear inclusion pathology occurs more frequently than cytoplasmic RBM45 inclusion pathology and exhibits cell type-specific variation. Collectively, our results define new stress-associated functions of RBM45, a mechanism for nuclear RBM45 inclusion formation, a role for NSBs in the pathogenesis of ALS, FTLD-TDP, and AD, and further underscore the importance of protein self-association to both the normal and pathological functions of RBPs in these diseases.