Skip to main content

Advertisement

SpringerLink
Log in

L116 Deletion in CSPα Promotes α-Synuclein Aggregation and Neurodegeneration

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Parkinsonism is a clinical syndrome that is caused by Parkinson’s disease (PD) and other neurodegenerative diseases. Here, we report a patient who exhibited progressive parkinsonism, epilepsy, and cognitive impairment and was diagnosed with adult-onset neuronal ceroid lipofuscinoses (ANCLs). The patient carries a mutation (p.Leu116 del) in the DNAJC5 gene that encodes cysteine string protein (CSPα). Since the patient shows typical parkinsonism and loss of dopamine transporter in the striatum, we investigated the effect of wild-type and L116del mutant CSPα on the aggregation of α-synuclein (α-syn) and neurotoxicity in vitro. Overexpression of wild-type CSPα attenuated the phosphorylation, ubiquitination, and aggregation of α-syn induced by α-syn fibrils. Moreover, wild-type CSPα inhibits oxidative stress and cell apoptosis and rescues inefficient SNARE complex formation induced by α-syn fibrils in SH-SY5Y cells. However, these protective effects of CSPα were abolished by the L116del mutation. Collectively, these results indicate that L116 deletion in CSPα promotes α-syn pathology and neurotoxicity. Boosting CSPα may be therapeutically useful for treating synucleinopathies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

All data generated or analyzed in this study are available in the published article.

Code Availability

Not applicable.

References

  1. Naseri N, Sharma M, Velinov M (2021) Autosomal dominant neuronal ceroid lipofuscinosis: clinical features and molecular basis. Clin Genet 99:111–118. https://doi.org/10.1111/cge.13829

    Article  CAS  PubMed  Google Scholar 

  2. Greaves J, Lemonidis K, Gorleku OA et al (2012) Palmitoylation-induced aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis. J Biol Chem 287:37330–37339. https://doi.org/10.1074/jbc.M112.389098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nosková L, Stránecký V, Hartmannová H et al (2011) Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am J Hum Genet 89:241–252. https://doi.org/10.1016/j.ajhg.2011.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Benitez BA, Alvarado D, Cai Y et al (2011) Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis. PLoS One 6:e26741. https://doi.org/10.1371/journal.pone.0026741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Benitez BA, Cairns NJ, Schmidt RE et al (2015) Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss. Acta Neuropathol Commun 3:73. https://doi.org/10.1186/s40478-015-0256-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Burgoyne RD, Morgan A (2015) Cysteine string protein (CSP) and its role in preventing neurodegeneration. Semin Cell Dev Biol 40:153–159. https://doi.org/10.1016/j.semcdb.2015.03.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Caló L, Hidari E, Wegrzynowicz M et al (2021) CSPα reduces aggregates and rescues striatal dopamine release in α-synuclein transgenic mice. Brain 144:1661–1669. https://doi.org/10.1093/brain/awab076

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sharma M, Burré J, Südhof TC (2011) CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. Nat Cell Biol 13:30–39. https://doi.org/10.1038/ncb2131

    Article  CAS  PubMed  Google Scholar 

  9. Tobaben S, Thakur P, Fernández-Chacón R et al (2001) A trimeric protein complex functions as a synaptic chaperone machine. Neuron 31:987–999. https://doi.org/10.1016/s0896-6273(01)00427-5

    Article  CAS  PubMed  Google Scholar 

  10. Garcia-Reitböck P, Anichtchik O, Bellucci A et al (2010) SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease. Brain 133:2032–2044. https://doi.org/10.1093/brain/awq132

    Article  PubMed  PubMed Central  Google Scholar 

  11. Levin J, Kurz A, Arzberger T et al (2016) The differential diagnosis and treatment of atypical parkinsonism. Dtsch Arztebl Int 113:61–69. https://doi.org/10.3238/arztebl.2016.0061

    Article  PubMed  PubMed Central  Google Scholar 

  12. Grammatopoulos TN, Outeiro TF, Hyman BT, Standaert DG (2007) Angiotensin II protects against alpha-synuclein toxicity and reduces protein aggregation in vitro. Biochem Biophys Res Commun 363:846–851. https://doi.org/10.1016/j.bbrc.2007.09.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chandra S, Gallardo G, Fernández-Chacón R et al (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383–396. https://doi.org/10.1016/j.cell.2005.09.028

    Article  CAS  PubMed  Google Scholar 

  14. Bozic M, Caus M, Rodrigues-Diez RR et al (2020) Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis. Nat Commun 11:1943. https://doi.org/10.1038/s41467-020-15732-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cadieux-Dion M, Andermann E, Lachance-Touchette P et al (2013) Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease. Clin Genet 83:571–575. https://doi.org/10.1111/cge.12020

    Article  CAS  PubMed  Google Scholar 

  16. Burneo JG, Arnold T, Palmer CA et al (2003) Adult-onset neuronal ceroid lipofuscinosis (Kufs disease) with autosomal dominant inheritance in Alabama. Epilepsia 44:841–846. https://doi.org/10.1046/j.1528-1157.2003.39802.x

    Article  PubMed  Google Scholar 

  17. Huang Q, Zhang Y-F, Li L-J et al (2022) Adult-onset neuronal ceroid lipofuscinosis with a novel DNAJC5 mutation exhibits aberrant protein palmitoylation. Front Aging Neurosci 14:829573. https://doi.org/10.3389/fnagi.2022.829573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yan M, Xiong M, Dai L et al (2022) Cofilin 1 promotes the pathogenicity and transmission of pathological α-synuclein in mouse models of Parkinson’s disease. NPJ Park Dis 8:1. https://doi.org/10.1038/s41531-021-00272-w

    Article  CAS  Google Scholar 

  19. Zhu LN, Qiao HH, Chen L et al (2018) SUMOylation of alpha-synuclein influences on alpha-synuclein aggregation induced by methamphetamine. Front Cell Neurosci 12:1–18. https://doi.org/10.3389/fncel.2018.00262

    Article  CAS  Google Scholar 

  20. Musgrove RE, Helwig M, Bae E-J et al (2019) Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer. J Clin Invest 129:3738–3753. https://doi.org/10.1172/JCI127330

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yang H, Zhang M, Shi J et al (2017) Brain-specific SNAP-25 deletion leads to elevated extracellular glutamate level and schizophrenia-like behavior in mice. Neural Plast 2017:. https://doi.org/10.1155/2017/4526417

  22. Velinov M, Dolzhanskaya N, Gonzalez M et al (2012) Mutations in the gene DNAJC5 cause autosomal dominant kufs disease in a proportion of cases: Study of the parry family and 8 other families. PLoS One 7:1–8. https://doi.org/10.1371/journal.pone.0029729

    Article  CAS  Google Scholar 

  23. Sharma M, Burré J, Bronk P et al (2012) CSPα knockout causes neurodegeneration by impairing SNAP-25 function. EMBO J 31:829–841. https://doi.org/10.1038/emboj.2011.467

    Article  CAS  PubMed  Google Scholar 

  24. Gorenberg EL, Chandra SS (2017) The role of co-chaperones in synaptic proteostasis and neurodegenerative disease. Front Neurosci 11:1–16. https://doi.org/10.3389/fnins.2017.00248

    Article  Google Scholar 

  25. Roosen DA, Blauwendraat C, Cookson MR, Lewis PA (2019) DNAJC proteins and pathways to parkinsonism. FEBS J 286:3080–3094. https://doi.org/10.1111/febs.14936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Diez-Ardanuy C, Greaves J, Munro KR et al (2017) A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis. Sci Rep 7:10. https://doi.org/10.1038/s41598-017-00036-8

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang Y-Q, Chandra SS (2014) Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1842:2136–2146. https://doi.org/10.1016/j.bbadis.2014.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Henderson MX, Wirak GS, Zhang Y-Q et al (2016) Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. Acta Neuropathol 131:621–637. https://doi.org/10.1007/s00401-015-1512-2

    Article  CAS  PubMed  Google Scholar 

  29. Bartels T, Choi JG, Selkoe DJ (2011) α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477:107–110. https://doi.org/10.1038/nature10324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang Z, Kang SS, Liu X et al (2017) Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson’s disease. Nat Struct Mol Biol 24:632–642. https://doi.org/10.1038/nsmb.3433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jang A, Lee HJ, Suk JE et al (2010) Non-classical exocytosis of α-synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem 113:1263–1274. https://doi.org/10.1111/j.1471-4159.2010.06695.x

    Article  CAS  PubMed  Google Scholar 

  32. Burré J, Sharma M, Tsetsenis T et al (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663–1667. https://doi.org/10.1126/science.1195227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047. https://doi.org/10.1126/science.276.5321.2045

    Article  CAS  PubMed  Google Scholar 

  34. Dai L, Wang J, He M et al (2021) Lovastatin alleviates α-synuclein aggregation and phosphorylation in cellular models of synucleinopathy. Front Mol Neurosci 14:682320. https://doi.org/10.3389/fnmol.2021.682320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Luk KC, Lee VM (2014) Addition of exogenous α-Synuclein Pre-formed fibrils to Primary.pdf. Nat Protoc 9:2135–2146. https://doi.org/10.1038/nprot.2014.143.Addition

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (No. 82271447 and 82071183), the National Key Research & Development Program of China (2019YFE0115900), and the Innovative Research Groups of Hubei Province (2022CFA026).

Author information

Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Tao Guo, Jing Xiong, Tingting Xiao, Lingyan Zhou, Juanfeng He, Min Deng, Zhaohui Zhang & Zhentao Zhang

  2. PET-CT/MRI Center, Faculty of Radiology and Nuclear Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Hongyan Feng & Lihong Bu

  3. Department of Nursing, Renmin Hospital of Wuhan University, Wuhan, China

    Yan Liu

  4. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430000, China

    Zhentao Zhang

Authors
  1. Tao Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongyan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lihong Bu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tingting Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lingyan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juanfeng He
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Min Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhaohui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhentao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Z.Z., Z.Z., and Y.L. conceived the project. T.G. performed the cellular experiments. J.X., T.X., and M.D. collected the clinical data. H.F. and L.B. performed MRI scanning. L.Z. and J.H. prepared plasmids.

Corresponding authors

Correspondence to Yan Liu, Zhaohui Zhang or Zhentao Zhang.

Ethics declarations

Ethics Approval and Consent to Participate

All animal procedures were performed under the Care and Use of Laboratory Animals guidelines and approved by the Guangdong Academy of Medical Sciences (ER-20200720).

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Tao Guo and Jing Xiong contributed equally to this work.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 221 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, T., Xiong, J., Feng, H. et al. L116 Deletion in CSPα Promotes α-Synuclein Aggregation and Neurodegeneration. Mol Neurobiol 61, 15–27 (2024). https://doi.org/10.1007/s12035-023-03552-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03552-z

Keywords

Search

Navigation