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A cell-permeable compound that protects against alpha-synuclein toxicity., A cell-permeable N-aryl benzimidazole (NAB) compound that protects against alpha-synuclein (alpha-syn) toxicity in yeast (0.625 to 10 µ,M), wt human alpha-syn-expressing C. elegans dopaminergic neurons (10 µ,M), human A53T alpha-syn-expressing rat DA neurons (0.1 µ,M), as well as in Parkinson's disease patients-derived neurons carrying AT53T alpha-syn or an alpha-syn triplication (5 to 40 µ,M) by restoring Nedd4 (mammalian)/Rsp5 (yeast) E3 ligase-dependent trafficking events, reducing alpha-syn-caused nitrosative and ER stress without affecting cellular alpha-syn level or Nedd4/Rsp5 ligase activity., A cell-permeable N-aryl benzimidazole (NAB) compound that protects against alpha-synuclein (alpha-syn) toxicity in yeast (0.625 to 10 µ,M), wt human alpha-syn-expressing C. elegans dopaminergic (DA) neurons (10 µ,M), human A53T alpha-syn-expressing rat DA neurons (0.1 µ,M), as well as in human neurons differentiated from iPSCs derived from Parkinson's disease (PD) patients carrying either AT53T alpha-syn or an alpha-syn triplication (5 to 40 µ,M) by restoring Nedd4 (mammalian)/Rsp5 (yeast) E3 ligase-dependent processes, including ER-to-Golgi, plasma membrane- and Golgi-to-vacuole/lysosome trafficking events, reducing alpha-syn-caused nitrosative and ER stress. NAB2 is also reported to inhibit the growth, but not viability, of non-alpha-syn-expressing yeast via the same mechanism of action (MOA) albeit at a lower potency (GI40 = 20.5 µ,M vs. EC40 = 4.5 µ,M against alpha-syn toxicity). Although the exact molecular mechanism is yet unknown, NAB2 does not affect cellular alpha-syn level or Nedd4/Rsp5 ligase activity.