Age-dependent synuclein pathology following traumatic brain injury in mice

Abstract

Synucleins (Syn), a family of synaptic proteins, includes α-Syn, which plays a pivotal role in Parkinson’s disease and related neurodegenerative diseases (synucleinopathies) by forming distinct brain pathologies (Lewy bodies and neurites). Since traumatic brain injury (TBI) is a poorly understood risk factor for Parkinson’s disease, we examined the effects of TBI in the young and aged mouse brain on α-, β-, and γ-Syn. Immunohistochemical analysis showed that brains from sham-injured young and aged mice had normal α- and β-Syn immunoreactivity (IR) in neuropil of cortex, striatum, and hippocampus with little or no γ-Syn IR. At 1 week post TBI, the aged mouse brain showed a transient increase of α- and β-Syn IR in the neuropil as well as an induction of γ-Syn IR in subcortical axons. This was associated with strong labeling of striatal axon bundles by antibodies to altered or nitrated epitopes in α-Syn as well as by antibodies to inducible nitric oxide synthase. However, these TBI-induced changes disappeared by 16 weeks post TBI, and altered Syn IR was not seen in young mice subjected to TBI nor in α-Syn knockout mice while Western blots confirmed that TBI induced transient alterations of α-Syn in the mouse brains. This model of age-dependent TBI-induced transient alterations in α-Syn provides an opportunity to examine possible links between TBI and mechanisms of disease in synucleinopathies.