Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

Susy Prieto Huarcaya, Alice Drobny, André R A Marques, Alessandro Di Spiezio, Jan Philipp Dobert, Denise Balta, Christian Werner, Tania Rizo, Lisa Gallwitz, Simon Bub, Iva Stojkovska, Nandkishore R Belur, Jens Fogh, Joseph R Mazzulli, Wei Xiang, Amitkumar Fulzele, Mario Dejung, Markus Sauer, Beate Winner, Stefan Rose-JohnPhilipp Arnold, Paul Saftig, Friederike Zunke

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Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagic as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the SNCA gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a CTSD-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance, but also restored endo-lysosome and autophagy function in human and murine neurons as well as tissue. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden.

Original languageEnglish
JournalAutophagy
DOIs
Publication statusE-pub ahead of print - 28 Apr 2022

Keywords

  • alpha-synuclein
  • cathepsin D
  • lysosomal degradation
  • lysosomal storage disorders
  • parkinson disease
  • synucleinopathies

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