Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity

Abstract

α-synuclein (α-syn) is a main component of Lewy bodies (LB) that occur in many neurodegenerative diseases, includingParkinson's disease (PD), dementia with LB (DLB) and multi-system atrophy. α-syn mutations or amplifications are responsible for a subset of autosomal dominant familial PD cases, and overexpression causes neurodegeneration and motor disturbances in animals. To investigate mechanisms for α-syn accumulation and toxicity, we studied a mouse model of lysosomal enzyme cathepsin D (CD) deficiency, and found extensive accumulation of endogenous α-syn in neurons without overabundance of α-syn mRNA. In addition to impaired macroautophagy, CD deficiency reduced proteasome activity, suggesting an essential role for lysosomal CD function in regulating multiple proteolytic pathways that are important for α-syn metabolism. Conversely, CD overexpression reduces α-syn aggregation and is neuroprotective against α-syn overexpression-induced cell death in vitro. In a C. elegans model, CD deficiency exacerbates α-syn accumulation while its overexpression is protective against α-syn-induced dopaminergic neurodegeneration. Mutated CD with diminished enzymatic activity or overexpression of cathepsins B (CB) or L (CL) is not protective in the worm model, indicating a unique requirement for enzymatically active CD. Our data identify a conserved CD function in α-syn degradation and identify CD as a novel target for LB disease therapeutics.

Systems biology of the autophagy-lysosomal pathway

“…13,14 Genetic models of cathepsin D-deficient animals accumulate alpha-synuclein and autophagic vesicles. [15][16][17] Both LAMP2 and cathepsin D mutations affect not only the lysosomes but also autophagy and lipid metabolism, [18][19][20] further emphasizing the potential value of an integrated analyses of genes, biological pathways and disease connections. Furthermore, loss-of-function mutations in NPC1 and NPC2 that encode lysosomal acid sphingomylenases lead to Niemann-Pick Type C (NPC) disease, with accumulation of cholesterol and other lipids in late endosomes and lysosomes in virtually every tissue including the brain.…”

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

“…In addition, multiple transgenic lines were generated to further characterize the role of other cathepsin family members in neuroprotection. We found that overexpression of Cathepsin B or Cathepsin L, as well as 2 enzymatic CD mutants, failed to protect worm DA neurons against α-syn neurodegenedration, demonstrating that this effect is both specific to CD and contingent based on its enzymatic function [31] (Fig. 3a).…”

“…3 The Caenorhabditis elegans α-synuclein model is predictive for gene analysis in dopamine (DA) neuroprotection assays (a). Gene products identified in mammalian systems can be further evaluated for efficacy in protecting DA neurons from α-synuclein-induced DA neurodegeneration by overexpression in C. elegans DA neurons [23,31]. (b) Yeast screens for suppressors of α-synuclein toxicity have yielded gene candidates that were subsequently examined in C. elegans and drosophila for the ability to reduce the neurodegeneration associated with α-synuclein overexpression.…”

Promoting Autophagic Clearance: Viable Therapeutic Targets in Alzheimer's Disease

“…Z-Phe-Aladiazomethylketone, a positive modulator of cathepsin B activity, reduces Aβ levels in 10-11-month-old APP mice with Swedish and Indiana mutations (APP Swe/Ind ) and in 20-22-month-old APP swedish /PS1ΔE9 mice, protects against synaptic degeneration, and mitigates behavioral deficits [212]. Similarly, cathepsin D, another lysosomal/endosomal enzyme, has been implicated in clearance of Lewy bodies in PD [220]. One way to pharmacologically enhance cathepsin B and D activity is by administering pharmacological chaperones similar to the ones used in lysosomal storage diseases [221].…”