Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis.
Amyotrophic Lateral Sclerosis
/ drug therapy
Animals
Brain
/ drug effects
Cell Differentiation
Cell Survival
/ drug effects
Disease Models, Animal
Humans
Hydrazones
/ chemical synthesis
Induced Pluripotent Stem Cells
/ cytology
Locomotion
/ drug effects
Male
Mice
Mice, Transgenic
Motor Neurons
/ drug effects
Neuroprotection
/ drug effects
Neuroprotective Agents
/ chemical synthesis
Protein Binding
/ drug effects
Protein Multimerization
Structure-Activity Relationship
Superoxide Dismutase-1
/ genetics
Vesicular Transport Proteins
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
31 07 2020
31 07 2020
Historique:
received:
26
07
2019
accepted:
02
07
2020
entrez:
2
8
2020
pubmed:
2
8
2020
medline:
10
9
2020
Statut:
epublish
Résumé
Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.
Identifiants
pubmed: 32737286
doi: 10.1038/s41467-020-17524-7
pii: 10.1038/s41467-020-17524-7
pmc: PMC7395176
doi:
Substances chimiques
Hydrazones
0
Neuroprotective Agents
0
VPS29 protein, human
0
VPS35 protein, human
0
Vesicular Transport Proteins
0
Sod1 protein, mouse
EC 1.15.1.1
Superoxide Dismutase-1
EC 1.15.1.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3848Références
Andersen, P. M. & Al-Chalabi, A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat. Rev. Neurol. 7, 603–615 (2011).
pubmed: 21989245
Blokhuis, A. M., Groen, E. J., Koppers, M., van den Berg, L. H. & Pasterkamp, R. J. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 125, 777–794 (2013).
pubmed: 23673820
pmcid: 3661910
Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).
pubmed: 8446170
Bruijn, L. I., Miller, T. M. & Cleveland, D. W. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27, 723–749 (2004).
pubmed: 15217349
Grad, L. I. et al. Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc. Natl Acad. Sci. USA 111, 3620–3625 (2014).
pubmed: 24550511
Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780–786 (2006).
pubmed: 17051204
Xie, Y. et al. Endolysosomal deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS mice. Neuron 87, 355–370 (2015).
pubmed: 26182418
pmcid: 4511489
Seaman, M. N. Recycle your receptors with retromer. Trends Cell Biol. 15, 68–75 (2005).
pubmed: 15695093
Seaman, M. N., McCaffery, J. M. & Emr, S. D. A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast. J. Cell Biol. 142, 665–681 (1998).
pubmed: 9700157
pmcid: 2148169
Feng, S. et al. The sorting nexin 3 retromer pathway regulates the cell surface localization and activity of a Wnt-activated polycystin channel complex. J. Am. Soc. Nephrol. 28, 2973–2984 (2017).
pubmed: 28620080
pmcid: 5619965
Bean, B. D., Davey, M. & Conibear, E. Cargo selectivity of yeast sorting nexins. Traffic 18, 110–122 (2017).
pubmed: 27883263
Gallon, M. et al. A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer. Proc. Natl Acad. Sci. USA 111, E3604–E3613 (2014).
pubmed: 25136126
Zhang, P., Wu, Y., Belenkaya, T. Y. & Lin, X. SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless. Cell Res. 21, 1677–1690 (2011).
pubmed: 22041890
pmcid: 3357989
Seaman, M. N., Marcusson, E. G., Cereghino, J. L. & Emr, S. D. Endosome to Golgi retrieval of the vacuolar protein sorting receptor, Vps10p, requires the function of the VPS29, VPS30, and VPS35 gene products. J. Cell Biol. 137, 79–92 (1997).
pubmed: 9105038
pmcid: 2139870
Arighi, C. N., Hartnell, L. M., Aguilar, R. C., Haft, C. R. & Bonifacino, J. S. Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J. Cell Biol. 165, 123–133 (2004).
pubmed: 15078903
pmcid: 2172094
Vilarino-Guell, C. et al. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89, 162–167 (2011).
pubmed: 21763482
pmcid: 3135796
Zimprich, A. et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168–175 (2011).
pubmed: 21763483
pmcid: 3135812
Zavodszky, E. et al. Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat. Commun. 5, 3828 (2014).
pubmed: 24819384
pmcid: 4024763
Tang, F. L. et al. VPS35 in dopamine neurons is required for ēndosome-to-Golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for alpha-synuclein degradation and prevention of pathogenesis of Parkinson’s disease. J. Neurosci. 35, 10613–10628 (2015).
pubmed: 26203154
pmcid: 4510296
Mecozzi, V. J. et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat. Chem. Biol. 10, 443–449 (2014).
pubmed: 24747528
pmcid: 4076047
Seaman, M. N. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J. Cell Biol. 165, 111–122 (2004).
pubmed: 15078902
pmcid: 2172078
Seaman, M. N. The retromer complex—endosomal protein recycling and beyond. J. Cell Sci. 125, 4693–4702 (2012).
pubmed: 23148298
pmcid: 3517092
Bhalla, A. et al. The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. Neurobiol. Dis. 47, 126–134 (2012).
pubmed: 22516235
pmcid: 3589992
Kerr, M. C. et al. A novel mammalian retromer component, Vps26B. Traffic 6, 991–1001 (2005).
pubmed: 16190980
Seaman, M. N. J. Retromer and its role in regulating signaling at endosomes. Prog. Mol. Subcell. Biol. 57, 137–149 (2018).
pubmed: 30097774
Convertino, M., Das, J. & Dokholyan, N. V. Pharmacological chaperones: design and development of new therapeutic strategies for the treatment of conformational diseases. ACS Chem. Biol. 11, 1471–1489 (2016).
pubmed: 27097127
Chourasiya, S. S. et al. Azine-hydrazone tautomerism of guanylhydrazones: evidence for the preference toward the azine tautomer. J. Org. Chem. 81, 7574–7583 (2016).
pubmed: 27494613
Diamant, S., Agranat, I., Goldblum, A., Cohen, S. & Atlas, D. Beta-adrenergic activity and conformation of the antihypertensive specific alpha 2-agonist drug, guanabenz. Biochem. Pharm. 34, 491–498 (1985).
pubmed: 2857565
Atkins, M. B. et al. A phase I study of CNI-1493, an inhibitor of cytokine release, in combination with high-dose interleukin-2 in patients with renal cancer and melanoma. Clin. Cancer Res. 7, 486–492 (2001).
pubmed: 11297238
Holmes, B., Brogden, R. N., Heel, R. C., Speight, T. M. & Avery, G. S. Guanabenz. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension. Drugs 26, 212–229 (1983).
pubmed: 6352237
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001).
pubmed: 11259830
Mayer, M. & Meyer, B. Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angew. Chem. Int. Ed. Engl. 38, 1784–1788 (1999).
pubmed: 29711196
Dalvit, C., Fogliatto, G., Stewart, A., Veronesi, M. & Stockman, B. WaterLOGSY as a method for primary NMR screening: practical aspects and range of applicability. J. Biomol. NMR 21, 349–359 (2001).
pubmed: 11824754
Williams, E. T. et al. Parkin mediates the ubiquitination of VPS35 and modulates retromer-dependent endosomal sorting. Hum. Mol. Genet. 27, 3189–3205 (2018).
pubmed: 29893854
pmcid: 6121197
Mourelatos, Z. et al. Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis revealed by organelle-specific antibodies. Proc. Natl Acad. Sci. USA 87, 4393–4395 (1990).
pubmed: 2349244
Urushitani, M., Ezzi, S. A., Matsuo, A., Tooyama, I. & Julien, J. P. The endoplasmic reticulum-Golgi pathway is a target for translocation and aggregation of mutant superoxide dismutase linked to ALS. FASEB J. 22, 2476–2487 (2008).
pubmed: 18337461
Fujita, Y. et al. Fragmentation of the Golgi apparatus of Betz cells in patients with amyotrophic lateral sclerosis. J. Neurol. Sci. 163, 81–85 (1999).
pubmed: 10223416
Sullivan, C. P. et al. Retromer disruption promotes amyloidogenic APP processing. Neurobiol. Dis. 43, 338–345 (2011).
pubmed: 21515373
pmcid: 3114192
Riva, N. et al. Defining peripheral nervous system dysfunction in the SOD-1G93A transgenic rat model of amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 73, 658–670 (2014).
pubmed: 24918640
Kluver, H. & Barrera, E. A method for the combined staining of cells and fibers in the nervous system. J. Neuropathol. Exp. Neurol. 12, 400–403 (1953).
pubmed: 13097193
Urushitani, M. et al. Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat. Neurosci. 9, 108–118 (2006).
pubmed: 16369483
Zhao, W. et al. Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia 58, 231–243 (2010).
pubmed: 19672969
pmcid: 2784168
Li, J. G., Chiu, J. & Pratico, D. Full recovery of the Alzheimer’s disease phenotype by gain of function of vacuolar protein sorting 35. Mol. Psychiatry https://doi.org/10.1038/s41380-019-0364-x (2019).
Li, J. G., Chiu, J., Ramanjulu, M., Blass, B. E. & Pratico, D. A pharmacological chaperone improves memory by reducing Abeta and tau neuropathology in a mouse model with plaques and tangles. Mol. Neurodegener. 15, 1 (2020).
pubmed: 31964406
pmcid: 6975032
Lane, R. F. et al. Vps10 family proteins and the retromer complex in aging-related neurodegeneration and diabetes. J. Neurosci. 32, 14080–14086 (2012).
pubmed: 23055476
pmcid: 3576841
Nielsen, M. S. et al. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. EMBO J. 20, 2180–2190 (2001).
pubmed: 11331584
pmcid: 125444
Laurent-Matha, V., Derocq, D., Prebois, C., Katunuma, N. & Liaudet-Coopman, E. Processing of human cathepsin D is independent of its catalytic function and auto-activation: involvement of cathepsins L and B. J. Biochem. 139, 363–371 (2006).
pubmed: 16567401
pmcid: 2376303
Miura, E. et al. VPS35 dysfunction impairs lysosomal degradation of alpha-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson’s disease. Neurobiol. Dis. 71, 1–13 (2014).
pubmed: 25107340
Wootz, H., Weber, E., Korhonen, L. & Lindholm, D. Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: possible roles in motor neuron survival. Neuroscience 143, 419–430 (2006).
pubmed: 16973300
Watanabe, M. et al. Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol. Dis. 8, 933–941 (2001).
pubmed: 11741389
Kabashi, E. et al. Proteasomes remain intact, but show early focal alteration in their composition in a mouse model of amyotrophic lateral sclerosis. J. Neurochem. 105, 2353–2366 (2008).
pubmed: 18315558
Shah, J. J. & Orlowski, R. Z. Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 23, 1964–1979 (2009).
pubmed: 19741722
pmcid: 4737506
Saxena, S., Cabuy, E. & Caroni, P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat. Neurosci. 12, 627–636 (2009).
pubmed: 19330001
Nakamura, N. et al. Characterization of a cis-Golgi matrix protein, GM130. J. Cell Biol. 131, 1715–1726 (1995).
pubmed: 8557739
Mourelatos, Z., Gonatas, N. K., Stieber, A., Gurney, M. E. & Dal Canto, M. C. The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. Proc. Natl Acad. Sci. USA 93, 5472–5477 (1996).
pubmed: 8643599
Cheng, X. T. et al. Characterization of LAMP1-labeled nondegradative lysosomal and endocytic compartments in neurons. J. Cell Biol. 217, 3127–3139 (2018).
pubmed: 29695488
pmcid: 6123004
Dahms, N. M., Olson, L. J. & Kim, J. J. Strategies for carbohydrate recognition by the mannose 6-phosphate receptors. Glycobiology 18, 664–678 (2008).
pubmed: 18621992
pmcid: 2733771
Duvvuri, M., Feng, W., Mathis, A. & Krise, J. P. A cell fractionation approach for the quantitative analysis of subcellular drug disposition. Pharm. Res. 21, 26–32 (2004).
pubmed: 14984254
Johnston, J. A., Dalton, M. J., Gurney, M. E. & Kopito, R. R. Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 97, 12571–12576 (2000).
pubmed: 11050163
Schagger, H. & von Jagow, G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal. Biochem. 199, 223–231 (1991).
pubmed: 1812789
Cullen, P. J. & Korswagen, H. C. Sorting nexins provide diversity for retromer-dependent trafficking events. Nat. Cell Biol. 14, 29–37 (2011).
pubmed: 22193161
pmcid: 3613977
Small, S. A. et al. Model-guided microarray implicates the retromer complex in Alzheimer’s disease. Ann. Neurol. 58, 909–919 (2005).
pubmed: 16315276
Oh, Y. K., Shin, K. S., Yuan, J. & Kang, S. J. Superoxide dismutase 1 mutants related to amyotrophic lateral sclerosis induce endoplasmic stress in neuro2a cells. J. Neurochem. 104, 993–1005 (2008).
pubmed: 18233996
Chen, B., Retzlaff, M., Roos, T. & Frydman, J. Cellular strategies of protein quality control. Cold Spring Harb. Perspect. Biol. 3, a004374 (2011).
pubmed: 21746797
pmcid: 3140689
Urushitani, M., Kurisu, J., Tsukita, K. & Takahashi, R. Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J. Neurochem. 83, 1030–1042 (2002).
pubmed: 12437574
Webster, C. P. et al. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 35, 1656–1676 (2016).
pubmed: 27334615
pmcid: 4969571
Corrionero, A. & Horvitz, H. R. A C9orf72 ALS/FTD ortholog acts in endolysosomal degradation and lysosomal homeostasis. Curr. Biol. 28, 1522–1535 e1525 (2018).
pubmed: 29731301
Gonatas, N. K. et al. Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis. Am. J. Pathol. 140, 731–737 (1992).
pubmed: 1546747
pmcid: 1886164
Nishimura, A. L. et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75, 822–831 (2004).
pubmed: 15372378
pmcid: 1182111
Teuling, E. et al. Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. J. Neurosci. 27, 9801–9815 (2007).
pubmed: 17804640
pmcid: 6672975
Dong, R. et al. Endosome-ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P. Cell 166, 408–423 (2016).
pubmed: 27419871
pmcid: 4963242
Stieber, A., Gonatas, J. O. & Gonatas, N. K. Aggregates of mutant protein appear progressively in dendrites, in periaxonal processes of oligodendrocytes, and in neuronal and astrocytic perikarya of mice expressing the SOD1(G93A) mutation of familial amyotrophic lateral sclerosis. J. Neurol. Sci. 177, 114–123 (2000).
pubmed: 10980307
Morris, G. M. et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 30, 2785–2791 (2009).
pubmed: 19399780
pmcid: 2760638
Hierro, A. et al. Functional architecture of the retromer cargo-recognition complex. Nature 449, 1063–1067 (2007).
pubmed: 17891154
pmcid: 2377034
Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).
pubmed: 8209258
Rossi, C. et al. Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis. Cell Death Dis. 9, 250 (2018).
pubmed: 29445154
pmcid: 5833860
Stevens, J. C. et al. Modification of superoxide dismutase 1 (SOD1) properties by a GFP tag–implications for research into amyotrophic lateral sclerosis (ALS). PLoS ONE 5, e9541 (2010).
pubmed: 20221404
pmcid: 2833207
Du, Z. W. et al. Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat. Commun. 6, 6626 (2015).
pubmed: 25806427
pmcid: 4375778