The formation of misfolded
protein aggregates is one of the pathological hallmarks of
neurodegenerative diseases. We have previously demonstrated the cytoplasmic aggregate formation of adenovirally expressed transactivation response
DNA-binding protein of 43 kDa (TDP-43), the main constituent of neuronal cytoplasmic aggregates in cases of
amyotrophic lateral sclerosis (ALS) and
frontotemporal lobar degeneration (
FTLD), in cultured neuronal cells under the condition of
proteasome inhibition. The TDP-43 aggregate formation was markedly suppressed by
co-infection of adenoviruses expressing
heat shock transcription factor 1 (HSF1), a master regulator of heat shock response, and Praja1 RING-finger
E3 ubiquitin ligase (PJA1) located downstream of the HSF1 pathway. In the present study, we examined other reportedly known E3
ubiquitin ligases for TDP-43, i.e. Parkin, RNF112 and RNF220, but failed to find their suppressive effects on neuronal cytoplasmic TDP-43 aggregate formation, although they all bind to TDP-43 as verified by co-immunoprecipitation. In contrast, PJA1 also binds to adenovirally expressed wild-type and mutated fused in
sarcoma,
superoxide dismutase 1, α-
synuclein and
ataxin-3, and huntingtin
polyglutamine proteins in neuronal cultures and suppressed the aggregate formation of these
proteins. These results suggest that PJA1 is a common sensing factor for aggregate-prone
proteins to counteract their aggregation propensity, and could be a potential therapeutic target for
neurodegenerative diseases that include ALS,
FTLD,
Parkinson's disease and
polyglutamine diseases.