Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice

Area of Science:

• Neuroscience
• Pathology
• Biochemistry

Background:

• Phosphorylation of alpha-synuclein (α-Synuclein) at serine 129 is a hallmark of Lewy bodies in Parkinson's disease (PD).
• The precise role of phosphorylated α-Synuclein in PD pathogenesis remains unclear due to conflicting in vivo data.

Purpose of the Study:

• To investigate the specific role of serine 129 phosphorylated α-Synuclein in driving PD pathology progression.
• To determine if phosphorylated α-Synuclein fibrils exacerbate neurodegeneration and motor deficits in a mouse model.

Main Methods:

• Stereotaxic injection of wild-type, phosphorylated S129, and non-phosphorylatable S129A α-Synuclein fibrils into the mouse striatum.
• Assessment of α-Synuclein seeding, inclusion formation, dopaminergic neuron loss, and motor function.
• Analysis of innate immune responses, including macrophage recruitment and cytokine release.

Main Results:

• All fibril types seeded endogenous α-Synuclein, but phosphorylated fibrils induced more inclusions in the Substantia Nigra pars compacta (SNpc).
• Injections of phosphorylated fibrils led to exacerbated cortical pathology, dopaminergic neuronal loss, and fine motor impairment by 60 days post-injection.
• Phosphorylation at S129 facilitated neuronal uptake of α-Synuclein fibrils and altered innate immune responses.

Conclusions:

• Phosphorylated α-Synuclein fibrils play a critical role in accelerating Parkinson's disease progression in vivo.
• Targeting phosphorylated α-Synuclein assemblies could be a therapeutic strategy to slow the formation of pathological inclusions.