Cathepsin D Replacement to Overcome Lysosomal Protease Deficiency

Mechanistic description

Mechanism / pathway

CTSD (cathepsin D)
→
proteomics

Evidence for (5)

Cathepsin D deficiency causes severe neurodegeneration with lysosomal storage accumulation

PMID:15282276
Cathepsin D expression and activity are reduced in aged brain and AD temporal lobe

PMID:25687867
Lysosomal pH becomes less acidic in aging neurons, impairing cathepsin activation

PMID:25695789
Cystamine/cysteamine increases cathepsin D activity and reduces aggregation in NCL models

PMID:24211030
Cathepsin D is major aspartic protease responsible for degrading protein aggregates in lysosomes

PMID:15657070

Evidence against (6)

Cathepsin D knockout mice paradoxically have enhanced Aβ deposition due to compensatory protease upregulation

PMID:15657070
Cathepsin D is required for α-synuclein fibril formation

PMID:29477463
Cathepsin D release from lysosomes triggers apoptosis

PMID:29477463
Cathepsin D processes neurotrophins (BDNF, NGF) - disruption may impair signaling

PMID:24211030
AAV delivery to aged neurons inefficient due to impaired trafficking - defeats strategy

PMID:25695789
No CNS enzyme replacement therapy exists for any lysosomal protease

PMID:24211030

Evidence matrix

5 supporting 6 contradicting

45% supporting

Supporting

Cathepsin D deficiency causes severe neurodegeneration with lysosomal storage accumulation PMID:15282276
Cathepsin D expression and activity are reduced in aged brain and AD temporal lobe PMID:25687867
Lysosomal pH becomes less acidic in aging neurons, impairing cathepsin activation PMID:25695789
Cystamine/cysteamine increases cathepsin D activity and reduces aggregation in NCL models PMID:24211030
Cathepsin D is major aspartic protease responsible for degrading protein aggregates in lysosomes PMID:15657070

Contradicting

Cathepsin D knockout mice paradoxically have enhanced Aβ deposition due to compensatory protease upregulation PMID:15657070
Cathepsin D is required for α-synuclein fibril formation PMID:29477463
Cathepsin D release from lysosomes triggers apoptosis PMID:29477463
Cathepsin D processes neurotrophins (BDNF, NGF) - disruption may impair signaling PMID:24211030
AAV delivery to aged neurons inefficient due to impaired trafficking - defeats strategy PMID:25695789
No CNS enzyme replacement therapy exists for any lysosomal protease PMID:24211030

Cite this hypothesis

Citation

etl-backfill (2026). Cathepsin D Replacement to Overcome Lysosomal Protease Deficiency. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-c27bd44a

BibTeX

@misc{scidex_hypothesis_hc27bd44,
  title        = {Cathepsin D Replacement to Overcome Lysosomal Protease Deficiency},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-c27bd44a},
  note         = {SciDEX artifact hypothesis:h-c27bd44a}
}