Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice

Abstract

α-Synuclein (α-syn) is a protein prevalent in neural tissue and known to undergo axonal transport. Intracellular α-syn aggregates are a hallmark of Parkinson’s disease (PD). Braak and collaborators have suggested that in people who are destined to eventually develop PD, α-syn aggregate pathology progresses following a stereotypic pattern, starting in the olfactory bulb (OB) and the gut. α-Synuclein aggregates are postulated to spread to interconnected brain regions over several years. Thus, propagation of the pathology via neural pathways can potentially explain how α-syn aggregates spread in PD. We have now studied if α-syn can transfer from the OB to other brain structures through neural connections, by injecting different molecular species of human α-syn (monomers, oligomers, fibrils) into the OB of wild-type mice. We found that non-fibrillar human α-syn is taken up very quickly by OB neurons. Within minutes to hours, it is also found in neurons in structures connected to the OB. Conversely, when we injected bovine serum albumin used as a control protein, we found that it does not diffuse beyond the OB, is rarely taken up by OB cells, and does not transfer to other structures. Taken together, our results show that OB cells readily take up α-syn, and that monomeric and oligomeric, but not fibrillar, forms of α-syn are rapidly transferred to interconnected structures within the timeframe we explored. Our results support the idea that α-syn can transfer along neural pathways and thereby contribute to the progression of the α-syn-related pathology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1160-3) contains supplementary material, which is available to authorized users.

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

“…This finding is similar to another study of intranasal administration of αS (25). Recently, Rey et al (47) have shown that injection of exogenous monomeric or aggregated αS in the mouse olfactory bulb can result in the transport to neurons of neuroanatomically connected brain regions, but the injected proteins had a short half-life (less than 72 h) and no induction of αS pathology was observed (47). Thus, it appears that the higher endogenous levels of αS in primed animals greatly accentuate the experimental peripheral induction of αS pathology.…”

Protease-resistant SOD1 aggregates in amyotrophic lateral sclerosis demonstrated by Paraffin Embedded Tissue (PET) blot

“…Comparable to prion diseases, in which the pathological prion protein propagates by a seeding/nucleation polymerization process and is transferred from cell to cell, stereotypic spread has been observed in e.g. synucleopathies and Alzheimer's disease [21][22][23][24]. For in vitro and in vivo studies and especially for the examination of the neuropathologically characteristic misfolded, oligomerized and aggregated proteins discrimination between normal and aberrant forms is essential.…”

α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

“…other neurodegenerative disorders (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). α-Synuclein is largely cytosolic, but readily binds to membranes, and associates with synaptic vesicles in the presynaptic terminal (22,23).…”

“…Moreover, α-synuclein is a major component of intracellular protein aggregates called Lewy bodies, which are pathological hallmarks of neurodegenerative disorders such as PD, Lewy body dementia, and multiple system atrophy (11)(12)(13)(14). Strikingly, neurotoxic α-synuclein aggregates propagate between neurons during neurodegeneration, suggesting that such α-synuclein aggregates are not only intrinsically neurotoxic but also nucleate additional fibrillization (15)(16)(17)(18).…”