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Ann Clin Transl Neurol. 2015 Jan;2(1):29-37. doi: 10.1002/acn3.143. Epub 2014 Dec 12.

Gamma-synuclein pathology in amyotrophic lateral sclerosis.

Author information

1
School of Biosciences, Cardiff University Museum Avenue, Cardiff, CF10 3AX, United Kingdom.
2
The Sheffield Institute for Translational Neuroscience 385A Glossop Road, Sheffield, S10 2HQ, United Kingdom.
3
Department of Clinical Neuroscience and MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, King's College London De Crespigny Park, London, SE5 8AF, United Kingdom.
4
School of Biosciences, Cardiff University Museum Avenue, Cardiff, CF10 3AX, United Kingdom ; Institute of General Pathology and Pathophysiology of Russian Academy of Medical Science 8 Baltijskaya str, Moscow, 125315, Russia.

Abstract

OBJECTIVE:

The prominent histopathological feature of the amyotrophic lateral sclerosis (ALS) is the presence of intracellular inclusions in degenerating neurons and their axons. The appearance and localization of these pathological structures depend on an aggregated protein that forms their scaffold. We investigated if γ-synuclein, an aggregation-prone protein highly expressed in healthy motor neurons, and predominantly localized in their axons and synaptic terminals is involved in ALS pathology.

METHODS:

Immunostaining of histological sections and sequential protein extraction from postmortem neural samples followed by immunoblotting.

RESULTS:

Immunohistochemical screening revealed a subset of sporadic (9 of 31) and familial (8 of 23) ALS cases with a novel type of pathology characterized by the accumulation of γ-synuclein in distinct profiles within the dorsolateral column. Sequential fractionation of proteins from the spinal cord tissues revealed detergent-insoluble γ-synuclein species specifically in the dorsolateral corticospinal tracts of a ALS patient with γ-synuclein-positive profiles in this region. These profiles are negative for protein markers commonly found in pathological inclusions in the spinal cord of ALS patients and most probably represent degenerated axons of upper motor neurons that have lost their neurofilaments. A subset of these profiles was found in association with phagocytic cells positive for Mac-2/Galectin-3. A smaller subset of studied ALS cases (4 of 54) contained large cytoplasmic inclusions in the cell body of remaining spinal motor neurons.

INTERPRETATION:

Our observations suggest that pathological aggregation of γ-synuclein might contribute to the pathogenesis of ALS.

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