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Although synthetic fibrils assembled form both tau and α-syn are able to mediate the transmission of pathologies, studies in primary neurons and transgenic mice suggest that α-syn may be more “transmissible” than tau (Guo and Lee, 2013; Iba et al., 2013; Luk et al., 2012b; Volpicelli-Daley et al., 2011). Robust α-syn pathology can be induced by α-syn pffs in wt neurons, whereas highly limited tau pathology occurs in wt neurons transduced with tau fibrils. Also, injection of α-syn pffs into the striatum and overlaying cortex of transgenic mice over-expressing mutant α-syn led to widespread LB-like pathology throughout the brain, but injection of tau pffs into exactly the same areas in transgenic mice over-expressing mutant tau resulted in spreading of NFT-like pathology to much more restricted brain regions. While these differences could be partly due to the A53T variant of α-syn naturally expressed in wt mouse (A53T mutation accelerates α-syn fibrillization and is pathogenic in human) and differential transgene expression in the two lines of transgenic mice used for injection studies, we cannot rule out the possibility that pathological α-syn is intrinsically more efficient than pathological tau in templating and propagating aggregation. In fact, this possibility is consistent with the findings that tau pathology is restricted to the brain in various tauopathies, but α-syn pathology appears to initiate from the peripheral and enteric nervous systems and spread all the way to the brain in PD (Braak and Del Tredici, 2009).

Several mechanisms could account for the superior transmissibility of α-syn: (1) α-syn has a higher propensity to fibrillize than tau as shown by in vitro studies. While α-syn readily assembles into fibrils without any co-factors, even seeded fibrillization of tau requires co-factors (Friedhoff et al., 1998). (2) In mature neurons, high local concentration of α-syn in the synaptic terminals may facilitate efficient templated recruitment. This is supported by experiments showing that pff-induced α-syn aggregation is first initiated in the axons before spreading to the cell bodies and dendrites, and the induction of pathology is far more efficient in more mature neuron cultures when α-syn concentration is higher in the axon terminals (Volpicelli-Daley et al., 2011). (3) Although the mechanism for cell-to-cell transmission of pathology is unknown, synaptic terminals

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are probable sites for interneuronal transfer of misfolded proteins. If this is true, the unique subcellular location α-syn gives it an advantage in transmission.

Another discrepancy between the transmission models of tauopathies vs. synucleinopathies is that α-syn aggregation, but not tau aggregation, is consistently accompanied by cell death, both in neurons and animal models. Toxicity associated with α-syn aggregation probably arises from filamentous aggregates themselves, which were shown to impair protein degradation machinery and block the axonal transport of selective cargoes that are critical for cell survival (unpublished data). Although the buildup of insoluble α-syn is accompanied by a concomitant reduction of soluble endogenous α-syn, which may result in loss-of-function toxicity, the observations that neurons derived from α-syn knock-out mice are perfectly healthy and α-syn knock-out mice do not show structural abnormalities (Abeliovich et al., 2000) argue against this possibility.

On the other hand, two major possibilities could explain the lack of toxicity of tau aggregates in the pff transduction/injection models. First, NFTs per se may be benign to cells, but in tauopathy brains, reduced MT stability due to loss of soluble tau to the NFTs is harmful for neurons. This hypothesis is consistent with behavioral deficits observed in aged tau KO mice despite a compensatory upregulation of MAP1A (Dawson et al., 2010; Harada et al., 1994; Ikegami et al., 2000; Lei et al., 2012). In the pff-transduced primary neurons derived from tau over-expressing mice, however, only a very small fraction of endogenous mouse tau gets recruited into the insoluble aggregates, and the minor loss of soluble endogenous tau can be easily compensated by over-expressed human tau, thus MT integrity is unlikely compromised in these cells, similarly in pff-injected transgenic mice. Unless robust aggregation of endogenous mouse tau can be induced in wt neurons/mice without tau over-expression, it would not be possible to observe the loss-of-function toxicity resulted from tau aggregation. Second, although fibrillar tau is able to induce and propagate pathology that is highly reminiscent of AD NFTs, the truly toxic species of tau may be distinct from the transmissible species. Studies on infectious

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prion particles have suggested a dissociation between infectivity and neurotoxicity (reviewed by Caughey and Lansbury, 2003; Sandberg et al., 2011), which may hold true for tau as well. It is possible that tau oligomers, instead of mature NFTs, are more toxic to cells. Tau pffs directly recruit soluble tau into filamentous aggregates and result in a complete bypassing of the slow oligomerization phase that normally occurs in uninjected transgenic mice prior to the onset of overt pathology. This in turn could explain the curious paradox of neuron loss in aged untreated mice bearing ThS-negative tau inclusions but not in pff-injected mice harboring more mature tangles.