Abstract
Synucleinopathies are neurodegenerative diseases in which α-synuclein protein accumulates in neurons and glia. In these diseases, α-synuclein forms dense intracellular aggregates that are disease hallmarks and actively contribute to tissue pathology. Interestingly, many pathological mechanisms, including iron accumulation and lipid peroxidation, are shared between classical synucleinopathies such as Alzheimer’s disease, Parkinson’s disease and traumatic spinal cord injury (SCI). However, to date, no studies have determined if α-synuclein accumulation occurs after human SCI. To examine this, cross-sections from injured and non-injured human spinal cords were immunolabeled for α-synuclein. This showed robust α-synuclein accumulation in profiles resembling axons and astrocytes in tissue surrounding the injury, revealing that α-synuclein markedly aggregates in traumatically injured human spinal cords. We also detected significant iron deposition in the injury site, a known catalyst for α-synuclein aggregation. Next a rodent SCI model mimicking the histological features of human SCI revealed aggregates and structurally altered monomers of α-synuclein are present after SCI. To determine if α-synuclein exacerbates SCI pathology, α-synuclein knockout mice were tested. Compared to wild type mice, α-synuclein knockout mice had significantly more spared axons and neurons and lower pro-inflammatory mediators, macrophage accumulation, and iron deposition in the injured spinal cord. Interestingly, locomotor analysis revealed that α-synuclein may be essential for dopamine-mediated hindlimb function after SCI. Collectively, the marked upregulation and long-lasting accumulation of α-synuclein and iron suggests that SCI may fit within the family of synucleinopathies and offer new therapeutic targets for promoting neuron preservation and improving function after spinal trauma.
Highlights
Synucleinopathies are neurodegenerative diseases in which α-synuclein protein accumulates in neurons and glia
If present after spinal cord injury (SCI), pathological α-synuclein would be in position to exacerbate tissue pathology through multiple mechanisms, such as elevated reactive oxygen species p roduction[26], mitochondrial impairment[27], and synaptic dysregulation[14]
Recent work using non-traumatic models of spinal cord injury (SCI) in lampreys and rabbits suggests that α-synuclein could contribute to tissue pathology and lack of r egeneration[28,29,30]
Summary
Synucleinopathies are neurodegenerative diseases in which α-synuclein protein accumulates in neurons and glia. Results show both robust α-synuclein and iron accumulation in acute human SCI tissue, with prominent staining of α-synuclein in damaged white matter and astrocyte-like profiles. Protein from rat traumatized spinal cords was probed for expression of monomeric α-synuclein, which revealed both truncated and elevated molecular weight isoforms from acute to chronic post-injury times.
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