. A β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain. Nat Commun. 2010;1:110. PubMed.

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  1. No doubt, dementia with Lewy bodies (DLB) is a complex disease with many possible factors contributing to the pathogenesis. Hashimoto and colleagues show that the P123H mutation in β-synuclein linked to DLB causes neurodegeneration in a mouse model, and this appears independent of α-synuclein. In terms of DLB genetics, only two familial mutations in DLB have been reported thus far, including α-synuclein E46K (Zarranz et al., 2004) and β-synuclein P123H (Ohtake et al., 2004), as well as one mutation, V70M, in an apparently sporadic case of DLB. In this context, the P123H mouse model is very important to demonstrate that the β-synuclein P123H mutation is pathogenic in an vivo animal model.

    It is still unclear how β-synuclein causes neurodegeneration in this model, but in terms of DLB, it may interact with other molecules other than α-synuclein, such as amyloid oligomers which are also found in DLB, resulting in neuronal toxicity (as in β-synuclein crossed with APP-overexpressing mice). Therefore, this model may be useful to further explore the biology and interactions of β-synuclein, and to provide insight into the etiologies of DLB.

    References:

    . The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004 Feb;55(2):164-73. PubMed.

    . Beta-synuclein gene alterations in dementia with Lewy bodies. Neurology. 2004 Sep 14;63(5):805-11. PubMed.

  2. For a long time, β-synuclein (βS) was considered to be a neuroprotective homolog of the cytotoxic, disease-causing α-synuclein (αS). However, this recent study by Fujita et al. demonstrates that the P123H βS mutation, associated with familial cases of dementia with Lewy bodies (DLB) is pathogenic in itself, causing neuronal degeneration, and learning and memory deficits in mice. In this study, the authors nicely show that P123H βS pathology is not affected by silencing the endogenous αS expression, supporting the occurrence of a unique mechanism of toxicity for βS mutation rather than loss of a protective effect of βS. Importantly, crossing these P123H βS mice with αS overexpressing mice that model the synucleinopathies resulted in enhanced neurodegeneration, suggesting that P123H βS may cooperate with pathogenic αS and accelerate its pathogenesis.

    While the nature of the association between αS and βS is still unresolved, growing evidence suggests a physical association between the two homologous proteins. βS was shown to normally occur in hetero-oligomers with αS in wild-type mouse brain (1) and in this way control polyunsaturated fatty acid (PUFA)-enhanced αS oligomerization (1). In addition, βS was shown to directly inhibit αS aggregation and protofibril formation in vitro (2-4).

    The authors state that the mechanism underlying the conversion from neuroprotective to neurotoxic βS by the single amino acid substitution P123H is unknown. One potential approach to understanding this pathogenic conversion may rely on elucidating the nature of βS association with brain lipids. While a role for brain lipids in αS pathogenesis is consolidating, only a limited number of studies focus on βS associations with lipids. This may be due to differences in the lipid-binding domains between αS and βS, and specifically, the deletion of 11 residues in the βS sequence affecting the degree of homology to the apolipoprotein A1 in the N-terminal region of the βS protein (5). Yet, in vivo, βS associates with lipids; it is found in purified myelin, and in additional lipid-rich fractions of the mouse brains (1,6-7).

    The direct involvement of βS in pathogenesis of DLB as shown in this study calls for revisiting the definition of the synucleinopathies, taking into account a role for βS alongside αS abnormalities.

    References:

    . Beta-synuclein occurs in vivo in lipid-associated oligomers and forms hetero-oligomers with alpha-synuclein. J Neurochem. 2009 Jan;108(2):465-74. PubMed.

    . beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron. 2001 Oct 25;32(2):213-23. PubMed.

    . Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J Biol Chem. 2002 Apr 5;277(14):11970-8. PubMed.

    . Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson's disease. Biochemistry. 2003 Apr 8;42(13):3696-700. PubMed.

    . Secondary structure and dynamics of micelle bound beta- and gamma-synuclein. Protein Sci. 2006 May;15(5):1162-74. PubMed.

    . Autoimmune encephalomyelitis and uveitis induced by T cell immunity to self beta-synuclein. J Immunol. 2003 Jan 1;170(1):628-34. PubMed.

    . An investigation into the lipid-binding properties of alpha-, beta- and gamma-synucleins in human brain and cerebrospinal fluid. Brain Res. 2007 Sep 19;1170:103-11. PubMed.

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