Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice

Misfolded alpha-synuclein may behave like a prion, changing the conformation of uncorrupted alpha-synuclein and self-propagating from neuron to neuron. Helwig et al. demonstrate inter-neuronal transfer of non-fibrillar forms of alpha-synuclein that can spread throughout the brain and induce neuronal injury, but without requiring a prion-like seeding and amplification mechanism.Misfolded alpha-synuclein may behave like a prion, changing the conformation of uncorrupted alpha-synuclein and self-propagating from neuron to neuron. Helwig et al. demonstrate inter-neuronal transfer of non-fibrillar forms of alpha-synuclein that can spread throughout the brain and induce neuronal injury, but without requiring a prion-like seeding and amplification mechanism.Aggregation and neuron-to-neuron transmission are attributes of alpha-synuclein relevant to its pathogenetic role in human synucleinopathies such as Parkinson's disease. Intraparenchymal injections of fibrillar alpha-synuclein trigger widespread propagation of amyloidogenic protein species via mechanisms that require expression of endogenous alpha-synuclein and, possibly, its structural corruption by misfolded conformers acting as pathological seeds. Here we describe another paradigm of long-distance brain diffusion of alpha-synuclein that involves inter-neuronal transfer of monomeric and/or oligomeric species and is independent of recruitment of the endogenous protein. Targeted expression of human alpha-synuclein was induced in the mouse medulla oblongata through an injection of viral vectors into the vagus nerve. Enhanced levels of intra-neuronal alpha-synuclein were sufficient to initiate its caudo-rostral diffusion that likely involved at least one synaptic transfer and progressively reached specific brain regions such as the locus coeruleus, dorsal raphae and amygdala in the pons, midbrain and forebrain. Transfer of human alpha-synuclein was compared in two separate lines of alpha-synuclein-deficient mice versus their respective wild-type controls and, interestingly, lack of endogenous alpha-synuclein expression did not counteract diffusion but actually resulted in a more pronounced and advanced propagation of exogenous alpha-synuclein. Self-interaction of adjacent molecules of human alpha-synuclein was detected in both wild-type and mutant mice. In the former, interaction of human alpha-synuclein with mouse alpha-synuclein was also observed and might have contributed to differences in protein transmission. In wild-type and alpha-synuclein-deficient mice, accumulation of human alpha-synuclein within recipient axons in the pons, midbrain and forebrain caused morphological evidence of neuritic pathology. Tissue sections from the medulla oblongata and pons were stained with different antibodies recognizing oligomeric, fibrillar and/or total (monomeric and aggregated) alpha-synuclein. Following viral vector transduction, monomeric, oligomeric and fibrillar protein was detected within donor neurons in the medulla oblongata. In contrast, recipient axons in the pons were devoid of immunoreactivity for fibrillar alpha-synuclein, indicating that non-fibrillar forms of alpha-synuclein were primarily transferred from one neuron to the other, diffused within the brain and led to initial neuronal injury. This study elucidates a paradigm of alpha-synuclein propagation that may play a particularly important role under pathophysiological conditions associated with enhanced alpha-synuclein expression. Rapid long-distance diffusion and accumulation of monomeric and oligomeric alpha-synuclein does not necessarily involve pathological seeding but could still result in a significant neuronal burden during the pathogenesis of neurodegenerative diseases.