Table 1.

Studies harnessing proteasome phosphoregulation to treat proteotoxicity

PDEs inhibited	Drugs	Disease models	Effects	References
PDE1	IC86430	Tg mice of DRC	Increase p-S14-Rpn6 and proteasome activities, improve cardiac diastolic function, and delay mouse premature death	[55]
PDE1	Dipyridamole	Cell model of PD	Reduce a-synuclein induced toxicity	[68]
PDE3	Cilostazol	AD patients	Reduce risk to develop dementia	[70]
PDE4	Rolipram	Tg mice of Tauopathy	Improve cognition with early-stage disease	[63]
PDE4	Piclamilast	Tg mice of DRC	Increase p-S14-Rpn6 and proteasome activities	[55]
PDE5	Sildenafil	Tg mice of DRC	Slow down disease progression	[50]
PDE5	Sildenafil	AD patients	Improve vascular and metabolic function	[69]
PDE10	Papaverine; PF-02545920	Tg mice of HD	Improve cognition and correct basal ganglion circuitry deficits	[65] [66]

AD, Alzheimer’s disease; DRC, desmin-related cardiomyopathy; HD, Huntington’s disease; PD, Parkinson’s disease; PDE, phosphodiesterase; p-S14-Rpn6, Ser14-phosphorylated Rpn6; Tg, transgenic