Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers.

Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers.

Publication date: Jun 05, 2019

In 2004 we described the E46K mutation in alpha-synuclein gene (E46K-SNCA), a rare point mutation causing an aggressive Lewy body disease with early prominent non-motor features and small fiber denervation of myocardium. Considering the potential interest of the skin as a target for the development of biomarkers in Parkinson’s Disease (PD), in this work we aimed to evaluate structural and functional integrity of small autonomic nerve fibers and phosphorylated alpha-synuclein (p-synuclein) deposition in the skin of E46K-SNCA carriers as compared to those observed in parkin gene mutation (PARK2) carriers and healthy controls.

We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic), 2 PARK2 carriers and 2 healthy controls to quantify intraepidermal nerve fiber density and p-synuclein deposition with cervical skin punch biopsies (immunohistochemistry against anti PGP9.5/UCHL-1, TH and p-synuclein) and sudomotor function with electrochemical skin conductance (ESC) (SudoScan).

All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with Pure Autonomic Failure, while p-synuclein aggregates where absent in healthy controls and in one of two PARK2 carriers. The severity of the latter skin abnormalities in E46K-SNCA were correlated with sudomotor dysfunction (lower ESC) in hands (p = 0.035).

These results together with our previous findings support the relevance of E46K-SNCA mutation as a suitable model to study small fiber neuropathy in Lewy body diseases.

Carmona-Abellan, M., , Gabilondo, Murueta-Goyena, A., , Khurana, Tijero, B., Luquin, Acera, M., Del Pino, R., Gardeazabal, J., , Mart’inez-Valbuena, Sanchez-Pernaute, R., and G’omez-Esteban, J.C. Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers. 21113. 2019 Parkinsonism Relat Disord.

Concepts Keywords
Asymptomatic Pure autonomic failure
Autonomic Sudomotor dysfunction
Biomarkers Branches of biology
Cervical Lewy body dementia
Dementia Proteins
Electrochemical Peripheral membrane proteins
Epidermal Neuropathology
Fascicles Parkinson’s disease
Fiber Alpha-synuclein
Immunohistochemistry Neurological disorders
Lewy Bodies SNCA
Mutation Alpha
Nerve Fiber
Point Mutation
Punch Biopsies
Skin Conductance


Type Source Name
disease MESH skin abnormalities
disease MESH pure autonomic failure
drug DRUGBANK Profenamine
drug DRUGBANK Trihexyphenidyl
disease MESH development
disease DOID Lewy body disease
disease MESH Lewy body disease
disease MESH point mutation
disease MESH Small fiber neuropathy


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