Mechanistic description
Cathepsin D Replacement to Overcome Lysosomal Protease Deficiency
Evidence for (5)
Cathepsin D deficiency causes severe neurodegeneration with lysosomal storage accumulation
Cathepsin D expression and activity are reduced in aged brain and AD temporal lobe
Lysosomal pH becomes less acidic in aging neurons, impairing cathepsin activation
Cystamine/cysteamine increases cathepsin D activity and reduces aggregation in NCL models
Cathepsin D is major aspartic protease responsible for degrading protein aggregates in lysosomes
Evidence against (6)
Cathepsin D knockout mice paradoxically have enhanced Aβ deposition due to compensatory protease upregulation
Cathepsin D is required for α-synuclein fibril formation
Cathepsin D release from lysosomes triggers apoptosis
Cathepsin D processes neurotrophins (BDNF, NGF) - disruption may impair signaling
AAV delivery to aged neurons inefficient due to impaired trafficking - defeats strategy
No CNS enzyme replacement therapy exists for any lysosomal protease