Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo

Cullen, Valerie; Lindfors, Maria; Ng, Janet; Paetau, Anders; Swinton, Erika; Kolodziej, Piotr; Boston, Heather; Säftig, Paul; Woulfe, John; Feany, Mel Β.; Myllykangas, Liisa; Schlossmacher, Michael G.; Tyynelä, Jaana

doi:10.1186/1756-6606-2-5

Cited by 256 publications

(285 citation statements)

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“…Changes in α ‐synuclein have been reported in many studies of Batten disease, particularly in CLN1 and CLN10 (cathepsin D) deficient mice (Cullen et al. 2009; Blom et al. 2013; Koch et al.…”

Section: Discussionmentioning

confidence: 99%

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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AimsSynapses represent a major pathological target across a broad range of neurodegenerative conditions. Recent studies addressing molecular mechanisms regulating synaptic vulnerability and degeneration have relied heavily on invertebrate and mouse models. Whether similar molecular neuropathological changes underpin synaptic breakdown in large animal models and in human patients with neurodegenerative disease remains unclear. We therefore investigated whether molecular regulators of synaptic pathophysiology, previously identified in Drosophila and mouse models, are similarly present and modified in the brain of sheep with CLN5 Batten disease.MethodsGross neuropathological analysis of CLN5 Batten disease sheep and controls was used alongside postmortem MRI imaging to identify affected brain regions. Synaptosome preparations were then generated and quantitative fluorescent Western blotting used to determine and compare levels of synaptic proteins.ResultsThe cortex was particularly affected by regional neurodegeneration and synaptic loss in CLN5 sheep, whilst the cerebellum was relatively spared. Quantitative assessment of the protein content of synaptosome preparations revealed significant changes in levels of seven out of eight synaptic neurodegeneration proteins investigated in the motor cortex, but not cerebellum, of CLN5 sheep (α‐synuclein, CSP‐α, neurofascin, ROCK2, calretinin, SIRT2, and UBR4).ConclusionsSynaptic pathology is a robust correlate of region‐specific neurodegeneration in the brain of CLN5 sheep, driven by molecular pathways similar to those reported in Drosophila and rodent models. Thus, large animal models, such as sheep, represent ideal translational systems to develop and test therapeutics aimed at delaying or halting synaptic pathology for a range of human neurodegenerative conditions.

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Section: Discussionmentioning

confidence: 99%

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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“…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.…”

Section: Resultsmentioning

confidence: 99%

Systems biology of the autophagy-lysosomal pathway

Jegga¹,

Schneider²,

Ouyang³

et al. 2011

Autophagy

113

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“…Cell culture experiments were carried out as described. 11,17,18 Transfection efficiency using Lipofectamine 2000 (Invitrogen, Carlsbad, CA) was determined by microscopy using a GFP-encoding cDNA plasmid in sister wells.…”

Section: Methodsmentioning

confidence: 99%

“…10 If confirmed in vivo, GSL-mediated sequestration of SNCA could lead to impaired access by its intracellular protease(s), referred to as synucleinase(s). Intriguingly, a recently detected candidate for promoting synucleinase activity in vivo, cathepsin D, [11][12][13] is postulated to be activated by rising ceramide concentrations. 14 According to this scenario, GCase activity loss could promote a net reduction in lysosomal ceramide, a downstream lowering of synucleinase activity, and-together with the rise in SNCA-binding GSL-the accumulation of intracellular SNCA.…”

mentioning

confidence: 99%

Acid β‐glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter α‐synuclein processing

Cullen

Sardi²,

et al. 2011

Annals of Neurology

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294

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Objective: Heterozygous mutations in the GBA1 gene elevate the risk of Parkinson disease and dementia with Lewy bodies; both disorders are characterized by misprocessing of a-synuclein (SNCA). A loss in lysosomal acid-bglucosidase enzyme (GCase) activity due to biallelic GBA1 mutations underlies Gaucher disease. We explored mechanisms for the gene's association with increased synucleinopathy risk. Methods: We analyzed the effects of wild-type (WT) and several GBA mutants on SNCA in cellular and in vivo models using biochemical and immunohistochemical protocols. Results: We observed that overexpression of all GBA mutants examined (N370S, L444P, D409H, D409V, E235A, and E340A) significantly raised human SNCA levels to 121 to 248% of vector control (p < 0.029) in neural MES23.5 and PC12 cells, but without altering GCase activity. Overexpression of WT GBA in neural and HEK293-SNCA cells increased GCase activity, as expected (ie, to 167% in MES-SNCA, 128% in PC12-SNCA, and 233% in HEK293-SNCA; p < 0.002), but had mixed effects on SNCA. Nevertheless, in HEK293-SNCA cells high GCase activity was associated with SNCA reduction by 32% (p ¼ 0.009). Inhibition of cellular GCase activity (to 8-20% of WT; p < 0.0017) did not detectably alter SNCA levels. Mutant GBA-induced SNCA accumulation could be pharmacologically reversed in D409V-expressing PC12-SNCA cells by rapamycin, an autophagy-inducer ( 40%; 10lM; p < 0.02). Isofagomine, a GBA chaperone, showed a related trend. In mice expressing two D409Vgba knockin alleles without signs of Gaucher disease (residual GCase activity, !20%), we recorded an age-dependent rise of endogenous Snca in hippocampal membranes (125% vs WT at 52 weeks; p ¼ 0.019). In young Gaucher disease mice (V394Lgbaþ/þ//prosaposin[ps]-null//ps-transgene), which demonstrate neurological dysfunction after age 10 weeks (GCase activity, 10%), we recorded no significant change in endogenous Snca levels at 12 weeks of age. However, enhanced neuronal ubiquitin signals and axonal spheroid formation were already present. The latter changes were similar to those seen in three week-old cathepsin D-deficient mice.Interpretation: Our results demonstrate that GBA mutants promote SNCA accumulation in a dose-and timedependent manner, thereby identifying a biochemical link between GBA1 mutation carrier status and increased synucleinopathy risk. In cell culture models, this gain of toxic function effect can be mitigated by rapamycin. Loss in GCase activity did not immediately raise SNCA concentrations, but first led to neuronal ubiquitinopathy and axonal spheroids, a phenotype shared with other lysosomal storage disorders. ANN NEUROL 2011;69:940-953 View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22400 Additional Supporting Information can be found in the online version of this article. 940

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Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo

Cited by 256 publications

References 74 publications

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

Systems biology of the autophagy-lysosomal pathway

Acid β‐glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter α‐synuclein processing

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