Skin nerve α-synuclein deposits in Parkinson’s disease and other synucleinopathies: a review



The in vivo diagnosis of synucleinopathies is an important research aim since clinical diagnostic criteria show low accuracy. The skin innervation, especially the autonomic subdivision, is a useful region to search for abnormal α-syn aggregates in synucleinopathies since the peripheral sympathetic nerves can be the earliest-affected neural region and autonomic symptoms may precede the classical symptoms of these disorders.


The major advantages of skin biopsy as an in vivo diagnostic tool for synucleinopathies are that it is an inexpensive and easy-to-perform technique requiring only limited facilities, and that it is repeatable in long-term studies as it causes only minor discomfort to the patient.


This review analyzes current progress in this area of research that may facilitate the standardization of this method, potentially eliminating differences among laboratories in the implementation of the method.


The most suitable and commonly used technique for identifying in vivo α-syn aggregates in skin nerves is indirect immunofluorescence, although several aspects of this approach need to be standardized, particularly when synucleinopathies without autonomic failure present a patchy distribution of abnormal α-syn aggregates in skin nerves. By contrast, synucleinopathies with autonomic failure may present widespread diffusion of abnormal aggregates in autonomic skin nerves.

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

Fig. 1a–b
Fig. 2A–B


  1. 1.

    George S, Rey NL, Reichenbach N, Steiner JA, Brundin P (2013) α-Synuclein: the long distance runner. Brain Pathol 23(3):350–357

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Dorsey ER, Constantinescu R, Thompson JP et al (2007) Projected number of 408. People with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68:384–386

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    McKeith IG, Dickson DW, Lowe J et al (2005) Consortium on DLB: diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872

  4. 4.

    Goldstein DS, Sharabi Y (2017) The heart of PD: Lewy body diseases as neurocardiologic disorders. Brain Res.

    Article  PubMed  Google Scholar 

  5. 5.

    Adler CH, Beach TG, Hentz JG et al (2014) Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology 83:406–412

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Rizzo G, Arcuti S, Copetti M, Alessandria M, Savica R, Fontana A, Liguori R, Logroscino G (2018) Accuracy of clinical diagnosis of dementia with Lewy bodies: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 89(4):358–366

    Article  Google Scholar 

  7. 7.

    Kaufmann H, Nahm K, Purohit D, Wolfe D (2004) Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 63(6):1093–1095

    Article  PubMed  Google Scholar 

  8. 8.

    Probst A, Bloch A, Tolnay M (2008) New insights into the pathology of Parkinson’s disease: does the peripheral autonomic system become central? Eur J Neurol 15(Suppl 1):1–4

    Article  PubMed  Google Scholar 

  9. 9.

    Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426

    Article  PubMed  Google Scholar 

  10. 10.

    Ikemura M, Saito Y, Sengoku R, Sakiyama Y, Hatsuta H, Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T, Fukayama M, Murayama S (2008) Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol 67(10):945–953

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG (2010) Arizona Parkinson’s Disease Consortium. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119(6):689–702

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Gelpi E, Navarro-Otano J, Tolosa E, Gaig C, Compta Y, Rey MJ, Martí MJ, Hernández I, Valldeoriola F, Reñé R, Ribalta T (2014) Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord 29(8):1010–1018

    Article  Google Scholar 

  13. 13.

    Gibbons CH, Wang N, Freeman R (2017) Cutaneous alpha-synuclein from paraffin embedded autopsy specimens in Parkinson’s disease. J Parkinsons Dis 7(3):503–509

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Miki Y, Tomiyama M, Ueno T, Haga R, Nishijima H, Suzuki C, Mori F, Kaimori M, Baba M, Wakabayashi K (2010) Clinical availability of skin biopsy in the diagnosis of Parkinson’s disease. Neurosci Lett 469(3):57–59

    Article  Google Scholar 

  15. 15.

    Wang N, Gibbons CH, Lafo J, Freeman R (2013) α-Synuclein in cutaneous autonomic nerves. Neurology 81(18):1604–1610

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Doppler K, Ebert S, Uçeyler N, Trenkwalder C, Ebentheuer J, Volkmann J, Sommer C (2014) Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology. Acta Neuropathol 128(1):99–109

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Donadio V, Incensi A, Cortelli P, Giannoccaro MP, Jaber MA, Baruzzi A, Liguori R (2013) Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure. Neurology 80(8):725–732

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Donadio V, Incensi A, Leta V, Giannoccaro MP, Scaglione C, Martinelli P et al (2014) Skin nerve α-synuclein deposits: a biomarker for idiopathic Parkinson disease. Neurology 82(15):1362–1369

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Donadio V, Incensi A, Piccinini C, Cortelli P, Giannoccaro MP, Baruzzi A, Liguori R (2016) Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease. Ann Neurol 79(2):306–316

    CAS  Article  Google Scholar 

  20. 20.

    Donadio V, Incensi A, Rizzo G, Capellari S, Pantieri R, Stanzani Maserati M, Devigili G, Eleopra R, Defazio G, Montini F, Baruzzi A, Liguori R (2017) A new potential biomarker for dementia with Lewy bodies: skin nerve α-synuclein deposits. Neurology 89(4):318–326

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Doppler K, Weis J, Karl K, Ebert S, Ebentheuer J, Trenkwalder C, Klebe S, Volkmann J, Sommer C (2015) Distinctive distrubution of phospho-alpha-synuclein in dermal nerves in multiple system atrophy. Mov Disord 30(12):1688–1692

    CAS  Article  Google Scholar 

  22. 22.

    Gibbons CH, Garcia J, Wang N, Shih LC, Freeman R (2016) The diagnostic discrimination of cutaneous α-synuclein deposition in Parkinson disease. Neurology 87(5):505–512

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Navarro-Otano J, Casanova-Mollà J, Morales M, Valls-Solé J, Tolosa E (2015) Cutaneous autonomic denervation in Parkinson’s disease. J Neural Transm (Vienna) 122(8):1149–1155

    Article  Google Scholar 

  24. 24.

    Zange L, Noack C, Hahn K, Stenzel W, Lipp A (2015) Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson’s disease from multiple system atrophy. Brain 138(Pt 8):2310–2321

    Article  Google Scholar 

  25. 25.

    Doppler K, Jentschke HM, Schulmeyer L, Vadasz D, Janzen A, Luster M, Höffken H, Mayer G, Brumberg J, Booij J, Musacchio T, Klebe S, Sittig-Wiegand E, Volkmann J, Sommer C, Oertel WH (2017) Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease. Acta Neuropathol 133(4):535–545

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Antelmi E, Donadio V, Incensi A, Plazzi G, Liguori R (2017) Skin nerve phosphosylated α-synuclein deposits in idiopathic REM sleep behavior disorder. Neurology 88(22):2128–2131

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Donadio V, Doppler K, Incensi A, Kuzkina A, Janzen A, Mayer G, Volkmann J, Rizzo G, Antelmi E, Plazzi G, Sommer C, Liguori R, Oertel WH (2018) Abnormal α-synuclein deposits in skin nerves: intra- and inter-laboratory reproducibility. Eur J Neurol (submitted)

  28. 28.

    Beach TG, White CL, Hamilton RL, Duda JE, Iwatsubo T, Dickson DW, Leverenz JB, Roncaroli F, Buttini M, Hladik CL, Sue LI, Noorigian JV, Adler CH (2008) Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta Neuropathol 116(3):277–288

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Shin C, Park SH, Yun JY, Shin JH, Yang HK, Lee HJ, Kong SH, Suh YS, Kim HJ, Jeon B (2018) Alpha-synuclein staining in non-neural structures of the gastrointestinal tract is non-specific in Parkinson disease. Parkinsonism Relat Disord. 55:15-–17.

    Article  Google Scholar 

  30. 30.

    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    CAS  Article  Google Scholar 

  31. 31.

    Lee JM, Derkinderen P, Kordower JH, Freeman R, Munoz DG, Kremer T, Zago W, Hutten SJ, Adler CH, Serrano GE, Beach TG (2017) The search for a peripheral biopsy indicator of α-synuclein pathology for Parkinson disease. J Neuropathol Exp Neurol 76(1):2–15

  32. 32.

    Donadio V, Incensi A, El-Agnaf O, Rizzo G, Vaikath N, Del Sorbo F, Scaglione C, Capellari S, Elia A, Stanzani Maserati M, Pantieri R, Liguori R (2018) Skin α-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study. Sci Rep 8(1):14246.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Donadio V, Incensi A, Del Sorbo F, Rizzo G, Infante R, Scaglione C, Modugno N, Fileccia N, Elia AE, Cencini F, Liguori R (2018) Skin nerve phosphorylated α-synuclein deposits in Parkinson’s disease with orthostatic hypotension. J Neuropathol Exp Neurol 77:942–949.

    CAS  Article  Google Scholar 

  34. 34.

    Donadio V, Incensi A, Rizzo G, Scaglione C, Capellari S, Fileccia E et al (2017) Spine topographical distribution of skin α-synuclein deposits in idiopathic Parkinson disease. J Neuropathol Exp Neurol 76:384–389

    CAS  Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Vincenzo Donadio.

Ethics declarations

Conflict of interest

There is no conflict of interest to report for this manuscript.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Donadio, V. Skin nerve α-synuclein deposits in Parkinson’s disease and other synucleinopathies: a review. Clin Auton Res 29, 577–585 (2019).

Download citation


  • Phosphorylated α-synuclein
  • Skin biopsy
  • Pure autonomic failure
  • Idiopathic Parkinson’s disease
  • Dementia with Lewy bodies