Gamma‐synuclein pathology in amyotrophic lateral sclerosis

Abstract

ObjectiveThe 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.MethodsImmunostaining of histological sections and sequential protein extraction from postmortem neural samples followed by immunoblotting.ResultsImmunohistochemical 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.InterpretationOur observations suggest that pathological aggregation of γ-synuclein might contribute to the pathogenesis of ALS.

Dimerization propensities of Synucleins are not predictive for Synuclein aggregation

“…Although some extranigral neuritic pathology was shown, human βS and γS have not been detected in Lewy structures or glial cytoplasmic inclusions of multiple system atrophy so far [30][31][32]. The general consensus in the field is that aggregation is a main pathogenic feature of human αS.…”

“…Interestingly, expression of human βS with a point mutation that was described in rare cases with DLB induced neurodegeneration in a transgenic mouse model of DLB [43,44]. Very recently, pathological aggregation of human γS was suggested to contribute to the pathogenesis of ALS [32].…”

Translational neuroscience and psychiatry: A conceptual analysis

“…As described above, in relation to medicine, translational science involves the various processes that take place to transform basic science discoveries to medical applications and then in turn to implementation of these to wider clinical practice. Translational neuroscience refers specifically to the basic sciences related to the brain and the central nervous system, for example, research exploring pathogenesis in motor neurone disease by examining intracellular aggregates …”

A Lewy-testes demencia klinikai és neuropatológiai jellemzői

“…Noha pontos funkciójuk nem ismert, lokalizációjuk alapján feltételezhető, hogy a szinapszisok fiziológiás szabályozásában vesznek részt [14]. Habár a β-és γ-szinuklein is felelős lehet neurodegeneratív kór-képek kialakulásáért [15], legtöbb bizonyíték az αSyn patognomikus szerepéről áll rendelkezésre, ezeket össze-foglalóan α-synucleinopathiáknak hívjuk. A megbetegedésekben jellegzetes a kóros mértékű αSyn-aggregátumok felhalmozódása a központi idegrendszer sejtjeiben (neuronok, gliasejtek).…”