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Lim Y, Kehm VM, Lee EB, Soper JH, Li C, Trojanowski JQ, Lee VM. α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies. J Neurosci. 2011 Jul 6;31(27):10076-87. PubMed.
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University of California, San Diego
Deciphering details of α-synuclein-induced pathology in the brain has been surprisingly challenging, and the data by Lim et al., 2011, using an inducible system driven by the CamKII-promoter offer significant insights. While there are many notable take-home messages in this exquisitely detailed study, of particular interest to us is the observation that levels of multiple presynaptic vesicular proteins (including transmembrane and peripherally associated proteins) are greatly diminished in boutons overexpressing α-synuclein. The authors posit that this phenomenon is “the likely anatomic substrate of memory dysfunction.”
As noted by Lim et al., we recently showed that modest increases in α-synuclein levels lead to global decreases in presynaptic vesicular protein levels—a phenomenon we termed "vacant synapses" (Scott et al., 2010). Although this was a straightforward observation of a simple and tractable model system that we generated, it was nevertheless deemed contentious (see ARF related news story). While the exact mechanisms by which excessive α-synuclein leads to decreases in presynaptic protein levels remains unclear, there now seems to be little doubt that reductions in presynaptic protein levels are a bona-fide pathologic consequence of excessive α-synuclein.
It is interesting to note that several recent studies have implicated excessive α-synuclein at the synapse as the early underlying pathologic substrate in disease. This is in contrast to the longstanding focus on perikaryal Lewy bodies that has dominated the field for decades. Given the unequivocal and robust localization of α-synuclein to presynaptic terminals, the clear induction of synaptic pathology by modest α-synuclein levels, and the relative paucity of somatic Lewy bodies in the vast majority of PD/DLB brains, combined with the presence of presynaptic α-synuclein aggregates in such brains, this seems a logical course of events and perhaps represents a paradigm shift in the field.
References:
Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci. 2010 Jun 16;30(24):8083-95. PubMed.
Northwestern University
The paper by Pablo Sardi et al. demonstrates that expression of exogenous glucocerebrosidase (GC) in mice can ameliorate some aspects of pathology observed in Gaucher's disease-like mice. This important finding is consistent with other studies, including our own (Mazzulli et al., 2011) showing that mutant GC contributes to α-synuclein accumulation and pathology. The study by Sardi et al. also suggests that gain of function of GC may play at least a partial role in disease pathogenesis. However, further detailed mechanistic studies will be required to elucidate the relative contribution of this pathway to disease pathogenesis. Importantly, the current study confirms that glucocerebrosidase is an important therapeutic target for the treatment of synucleinopathies.
The paper by Virginia Lee’s group is an elegant study of reversibility of α-synuclein pathology when expression of α-synuclein is suppressed. This important finding highlights the role of α-synuclein accumulation and clearance in disease pathogenesis. It will be of interest to examine the mechanism of α-synuclein clearance in these mouse models and identify factors that either promote disaggregation of the pre-formed α-synuclein aggregates and/or prevent the formation of new oligomeric or aggregate species of α-synuclein. Identification of such factors that ultimately mediate removal of excessive α-synuclein from affected cells would facilitate the development of new therapies for PD and related synucleinopathies.
The first example of reversibility in accumulation and toxicity of aggregation-prone proteins has been shown in mouse models of Huntington’s disease (Yamamoto et al., 2000), and later, Harry Orr’s group demonstrated partial reversibility in mouse models of SCA1 (Zu et al., 2004). In addition, a similar phenomenon was observed in models of prion disease (Mallucci et al., 2003). Together with the nice study by Dr. Lee, these studies suggest that various forms of aggregation-prone proteins, such as monomers, oligomers, and aggregates, exist in some sort of equilibrium if the production of the monomeric form is maintained. However, when expression of monomeric forms is suppressed, these other moieties are amenable to degradation by cellular degradation machinery. Further mechanistic dissection of these pathways will be critical for future therapeutic development.
References:
Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. Epub 2011 Jun 23 PubMed.
Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell. 2000 Mar 31;101(1):57-66. PubMed.
Zu T, Duvick LA, Kaytor MD, Berlinger MS, Zoghbi HY, Clark HB, Orr HT. Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice. J Neurosci. 2004 Oct 6;24(40):8853-61. PubMed.
Mallucci G, Dickinson A, Linehan J, Klöhn PC, Brandner S, Collinge J. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science. 2003 Oct 31;302(5646):871-4. PubMed.
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