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Lysosomal gene deficiencies cause lysosomal storage disorders, many of which involve neurodegeneration. Heterozygous mutations of some of these genes, such as<jats:italic>GBA1<\/jats:italic>, are associated with PD.<jats:italic>CTSD<\/jats:italic>is the gene encoding Cathepsin D (CTSD), a lysosomal protein hydrolase, and homozygous CTSD deficiency results in neuronal ceroid-lipofuscinosis, which is characterized by the early onset, progressive neurodegeneration. CTSD deficiency was also associated with deposition of<jats:italic>\u03b1<\/jats:italic>-synuclein aggregates, the hallmark of PD. However, whether partial deficiency of CTSD has a role in the late onset progressive neurodegenerative disorders, including PD, remains unknown. Here, we generated cell lines harboring heterozygous nonsense mutations in<jats:italic>CTSD<\/jats:italic>with genomic editing using the zinc finger nucleases. Heterozygous mutation in<jats:italic>CTSD<\/jats:italic>resulted in partial loss of CTSD activity, leading to reduced lysosomal activity. The<jats:italic>CTSD<\/jats:italic>mutation also resulted in increased accumulation of intracellular<jats:italic>\u03b1<\/jats:italic>-synuclein aggregates and the secretion of the aggregates. When<jats:italic>\u03b1<\/jats:italic>-synuclein was introduced in the media, internalized<jats:italic>\u03b1<\/jats:italic>-synuclein aggregates accumulated at higher levels in CTSD+\/\u2212 cells than in the wild-type cells. Consistent with these results, transcellular transmission of<jats:italic>\u03b1<\/jats:italic>-synuclein aggregates was increased in CTSD+\/\u2212 cells. The increased transmission of<jats:italic>\u03b1<\/jats:italic>-synuclein aggregates sustained during the successive passages of CTSD+\/\u2212 cells. These results suggest that partial loss of CTSD activity is sufficient to cause a reduction in lysosomal function, which in turn leads to<jats:italic>\u03b1<\/jats:italic>-synuclein aggregation and propagation of the aggregates.<\/jats:p>","DOI":"10.1038\/cddis.2015.283","type":"journal-article","created":{"date-parts":[[2015,10,8]],"date-time":"2015-10-08T12:46:14Z","timestamp":1444308374000},"page":"e1901-e1901","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Haploinsufficiency of cathepsin D leads to lysosomal dysfunction and promotes cell-to-cell transmission of \u03b1-synuclein aggregates"],"prefix":"10.1038","volume":"6","author":[{"given":"E-J","family":"Bae","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N Y","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H-J","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S-J","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,8]]},"reference":[{"key":"BFcddis2015283_CR1","doi-asserted-by":"publisher","first-page":"e417","DOI":"10.1371\/journal.pbio.0040417","volume":"4","author":"MA Rujano","year":"2006","unstructured":"Rujano MA, Bosveld F, Salomons FA, Dijk F, van Waarde MA, van der Want JJ et al. 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