Consequence of Cathepsin D deficiencies. Cathepsin D is a major proteolytic enzyme in the lysosome. It cleaves α-synuclein in vitro and in cultured cells. Cathepsin D deficiency in human patients led to accumulation of lipofuscin and a prototype lysosomal storage disorder. Cathepsin D deficient worms, flies, mice, sheep and human patients exhibit increased α-synuclein accumulation and toxicity. Other associated cellular dysfunctions include: accumulation of autophagosomes, increased levels of Atg7, UCHL1, Park2, Cathepsin B, L, F, and H mRNAs, increased GAPDH and MEF2D proteins, impairment of proteasomal activities, and accumulation of ubiquitinated proteins. Overexpression of Cathepsin D in worms, flies, and mammalian cells has been shown to reduce α-synuclein aggregation and toxicity, suggesting a new approach to design future effective therapies.