Haploinsufficiency of Cathepsin D Leads to Lysosomal Dysfunction and Promotes Cell-To-Cell Transmission of α-synuclein Aggregates

Cell Death Dis. 2015 Oct 8;6(10):e1901. doi: 10.1038/cddis.2015.283.

Abstract

Lysosomal dysfunction has been implicated both pathologically and genetically in neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease (PD). Lysosomal gene deficiencies cause lysosomal storage disorders, many of which involve neurodegeneration. Heterozygous mutations of some of these genes, such as GBA1, are associated with PD. CTSD 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 α-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 CTSD with genomic editing using the zinc finger nucleases. Heterozygous mutation in CTSD resulted in partial loss of CTSD activity, leading to reduced lysosomal activity. The CTSD mutation also resulted in increased accumulation of intracellular α-synuclein aggregates and the secretion of the aggregates. When α-synuclein was introduced in the media, internalized α-synuclein aggregates accumulated at higher levels in CTSD+/- cells than in the wild-type cells. Consistent with these results, transcellular transmission of α-synuclein aggregates was increased in CTSD+/- cells. The increased transmission of α-synuclein aggregates sustained during the successive passages of CTSD+/- cells. These results suggest that partial loss of CTSD activity is sufficient to cause a reduction in lysosomal function, which in turn leads to α-synuclein aggregation and propagation of the aggregates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cathepsin D / genetics*
  • Cell Line, Tumor
  • Codon, Nonsense
  • Gaucher Disease / enzymology
  • Gaucher Disease / genetics
  • Haploinsufficiency
  • Humans
  • Lysosomes / enzymology*
  • Protein Aggregates
  • Protein Transport
  • alpha-Synuclein / metabolism*

Substances

  • Codon, Nonsense
  • Protein Aggregates
  • alpha-Synuclein
  • CTSD protein, human
  • Cathepsin D