title: Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice.
abstract: Aggregation and neuron-to-neuron transmission are attributes of α-synuclein relevant to its pathogenetic role in human synucleinopathies such as Parkinson's disease. Intraparenchymal injections of fibrillar α-synuclein trigger widespread propagation of amyloidogenic protein species via mechanisms that require expression of endogenous α-synuclein and, possibly, its structural corruption by misfolded conformers acting as pathological seeds. Here we describe another paradigm of long-distance brain diffusion of α-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 α-synuclein was induced in the mouse medulla oblongata through an injection of viral vectors into the vagus nerve. Enhanced levels of intra-neuronal α-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 α-synuclein was compared in two separate lines of α-synuclein-deficient mice versus their respective wild-type controls and, interestingly, lack of endogenous α-synuclein expression did not counteract diffusion but actually resulted in a more pronounced and advanced propagation of exogenous α-synuclein. Self-interaction of adjacent molecules of human α-synuclein was detected in both wild-type and mutant mice. In the former, interaction of human α-synuclein with mouse α-synuclein was also observed and might have contributed to differences in protein transmission. In wild-type and α-synuclein-deficient mice, accumulation of human α-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) α-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 α-synuclein, indicating that non-fibrillar forms of α-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 α-synuclein propagation that may play a particularly important role under pathophysiological conditions associated with enhanced α-synuclein expression. Rapid long-distance diffusion and accumulation of monomeric and oligomeric α-synuclein does not necessarily involve pathological seeding but could still result in a significant neuronal burden during the pathogenesis of neurodegenerative diseases.
authors.affiliation: 1 German Centre for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Helwig
authors.affiliation: 1 German Centre for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Klinkenberg
authors.affiliation: 1 German Centre for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rusconi
authors.affiliation: 1 German Centre for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Musgrove
authors.affiliation: 2 Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Tawam Medical Campus, Khalifa Ibn Zayed street, Al-Ain, United Arab Emirates.
authors.forename: Nour K
authors.initials: NK
authors.lastname: Majbour
authors.affiliation: 3 College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Education City, P.O. Box 5825 Doha, Qatar.
authors.forename: Omar M A
authors.initials: OM
authors.lastname: El-Agnaf
authors.affiliation: 1 German Centre for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Ayse
authors.initials: A
authors.lastname: Ulusoy
authors.affiliation: 1 German Centre for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany donato.dimonte@dzne.de.
authors.forename: Donato A
authors.initials: DA
authors.lastname: Di Monte
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Parkinson’s disease; adeno-associated virus; fibrils; oligomers; vagus nerve