Skin nerve α-synuclein deposits
A biomarker for idiopathic Parkinson disease
Abstract
Objective:
To investigate (1) whether phosphorylated α-synuclein deposits in skin nerve fibers might represent a useful biomarker for idiopathic Parkinson disease (IPD), and (2) the underlying pathogenesis of peripheral neuropathy associated with IPD.
Methods:
Twenty-one well-characterized patients with IPD were studied together with 20 patients with parkinsonisms assumed not to have α-synuclein deposits (PAR; 10 patients fulfilling clinical criteria for vascular parkinsonism, 6 for tauopathies, and 4 with parkin mutations) and 30 controls. Subjects underwent nerve conduction velocities from the leg to evaluate large nerve fibers and skin biopsy from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein considered the pathologic form of α-synuclein.
Results:
Patients with IPD showed a small nerve fiber neuropathy prevalent in the leg with preserved large nerve fibers. PAR patients showed normal large and small nerve fibers. Phosphorylated α-synuclein was not found in any skin sample in PAR patients and controls, but it was found in all patients with IPD in the cervical skin site. Abnormal deposits were correlated with leg epidermal denervation.
Conclusions:
The search for phosphorylated α-synuclein in proximal peripheral nerves is a sensitive biomarker for IPD diagnosis, helping to differentiate IPD from other parkinsonisms. Neuritic inclusions of α-synuclein were correlated with a small-fiber neuropathy, suggesting their direct role in peripheral nerve fiber damage.
Classification of evidence:
This study provides Class III evidence that the presence of phosphorylated α-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.
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© 2014 American Academy of Neurology.
Publication History
Received: August 30, 2013
Accepted: January 9, 2014
Published online: March 14, 2014
Published in print: April 15, 2014
Disclosure
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Study Funding
No targeted funding reported.
Authors
Author Contributions
V. Donadio: drafting/revising the manuscript, study concept and design, analysis and interpretation of data, study supervision. A. Incensi, V. Leta, M.P. Giannoccaro, and C. Scaglione: study concept and design, analysis and interpretation of data. P. Martinelli: drafting/revising the manuscript, study concept and design, analysis and interpretation of data. S. Capellari and P. Avoni: study concept and design, analysis and interpretation of data. A. Baruzzi: analysis and interpretation of data, study supervision. R. Liguori: drafting/revising the manuscript, study concept and design, analysis and interpretation of data, study supervision.
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- Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?, Frontiers in Molecular Neuroscience, 16, (2023).https://doi.org/10.3389/fnmol.2023.1197853
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We thank Dr. Sharma for his kind comments and agree that our data might contribute to standardize skin biopsy as a tool for the diagnosis of idiopathic Parkinson Disease, particularly regarding the site of biopsy. [1] Unlike Wang et al. [2] and Devic et al., [3] we found no correlation between abnormal synuclein deposits and clinical picture. Although further studies are need to clarify these conflicting findings, a possible explanation could be related to a different approach. We showed abnormal deposits of synuclein in peripheral nerves. [1] In the other studies, the expression of native synuclein protein was evaluated in skin nerves [2] or saliva. [3]
1. Donadio V, Incensi A, Leta V, et al. Skin nerve ?-synuclein deposits: A biomarker for idiopathic Parkinson disease. Neurology. 2014 Mar 14. [Epub ahead of print]
2. Wang N, Gibbons CH, Lafo J, et al. ?-Synuclein in cutaneous autonomic nerves. Neurology 2013;81:1604-1610.
3. Devic I, Hwang H, Edgar JS, et al. Salivary ?-synuclein and DJ-1: potential biomarkers for Parkinson's disease. Brain 2011;134:e178.
For disclosures, please contact the editorial office at [email protected].
Donadio et al. should be congratulated for their study [1] as reliable biomarkers for Parkinson disease (PD) are needed. Alpha-synuclein is a major constituent of Lewy bodies and the levels in CSF/serum/plasma have been proposed as potential biomarkers for PD. However, most investigations have drawbacks including difficulty in collecting CSF samples and blood contamination. Although skin biopsy for alpha-synuclein has been studied with varied conclusions [2, 3], Donadio et al.???s findings are encouraging. They demonstrated that only 52% and 24% of the skin samples from thigh and leg respectively were positive for phosphorylated alpha-synuclein. This should prompt standardization of skin biopsy procedures in PD patients, especially with respect to biopsy site. Correlating the presence and levels of alpha-synuclein with the clinical picture of PD is highly debated. While the authors failed to show any such correlation [1], Wang et al. found higher alpha-synuclein deposits in cutaneous autonomic nerves associated with more advanced PD. [2] Alpha-synuclein has also been shown in the saliva of PD patients and salivary alpha-synuclein correlated with UPDRS motor scores. [4]
1. Donadio V, Incensi A, Leta V, et al. Skin nerve ?-synuclein deposits: A biomarker for idiopathic Parkinson disease. Neurology. 2014 Mar 14. [Epub ahead of print]
2.Wang N, Gibbons CH, Lafo J, et al. ?-Synuclein in cutaneous autonomic nerves. Neurology 2013;81:1604-1610.
3. Michell AW, Luheshi LM, Barker RA. Skin and platelet alpha- synuclein as peripheral biomarkers of Parkinson's disease. Neurosci Lett 2005;381:294-298.
4. Devic I, Hwang H, Edgar JS, et al. Salivary ?-synuclein and DJ-1: potential biomarkers for Parkinson's disease. Brain 2011;134:e178.
For disclosures, please contact the editorial office at [email protected].