. CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12101-6. PubMed.


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  1. Pablo Sardi and colleagues did an excellent job describing the GBA
    mouse model; however, the data/experimental design could not decipher the central
    conundrum, i.e., whether GBA mutations act through a loss of function or a
    toxic gain of function. The authors speculate that glucocerebrosidase replacement may be a
    strategy for the treatment of α-synucleinopathies. This is tautology in the
    paper, but with merit for select patients where GBA mutations can be
    ascribed as a major contributor to disease.

    Sardi et al. did not address the mechanism in the context of past gene discovery, or the new synthesis emerging. Readers may be aware that we recently identified pathogenic mutations in VPS35, a
    central retromer component, in late-onset Parkinson's disease. The paper by
    Vilarino-Guell and colleagues is embargoed in American Journal of Human
    Genetics until 14 July 2011. My reason for mentioning it briefly is that the
    retromer is required to recycle mannose-6-phosphate receptors (MPR) that are
    necessary to traffic lysosomal enzymes, including glucocerebrosidase, from
    the Golgi complex to an acidified (pre)lysosomal compartment.

    Of note, the endosome Rab7L1 (which we postulate explains the PARK16 GWAS signal) is also
    required for proper MPR trafficking and for retromer localization and
    function. Dynactin and tau have also been directly implicated in retromer
    formation and parkinsonism. α-synuclein has been shown to more generally
    disrupt cellular Rab homeostasis, in a dose-dependent manner, and may affect
    multiple trafficking steps between the ER and Golgi. Likewise, LRRK2 GTPase
    and kinase signalling/scaffolding functions are most consistent with its
    complex being a master regulator of membrane protein trafficking.

    Many specific details need to be resolved, but GBA, VPS35, Rab7L1, DCTN1, MAPT, SNCA, and LRRK2—indeed most of the major
    genes identified in late-onset parkinsonism (to date)—now elucidate an
    overlapping biologic network. The phenomenology of selective vulnerability,
    variable expressivity, and penetrance may be addressed using a similar

    Ultimately, successful neuroprotective therapeutics for neurodegenerative
    disorders will result from a combination of genetic insight and model
    development, and Pablo Sardi's work nicely illustrates the approach.

  2. This PNAS paper represents the latest in a recent flurry of papers (Xu et al., 2010; Cullen et al., 2011; Mazzulli et al., 2011) examining the biochemical and mechanistic links between GBA mutations and synuclein mismetabolism. In the current paper, Sardi et al. find that mice carrying two copies of the D409V mutation in GBA exhibit progressive mismetabolism of synuclein and generalized ubiquitinopathy.

    We made the same observation in these mice in our recent Annals of Neurology paper (Cullen et al., 2011), where we showed an age-dependent increase in the synuclein content of the membrane fraction (containing within it the lysosomal compartment) and ubiquitin staining. Like Sardi et al., we also observed that mice carrying only one copy of the D409V mutation had subtle changes in synuclein levels, supporting the notion of a gain-of-toxic function as at least one aspect of the mechanistic interplay between GBA and synuclein.

    We also showed an accumulation of synuclein in simple cell models when D409V or the similar variant, D409H, was overexpressed. Importantly, when we overexpressed wild-type GBA in cells, we observed a significant reduction in cellular synuclein levels. This was the case in both PC12 cells, which were transfected with GBA, and in HEK293 cells, which experienced a more robust increase in GBA expression and activity due to viral overexpression.

    Sardi et al. have now extended our observations into animals by showing that viral overexpression of wild-type GBA into rodent brain can reduce the synuclein accumulation and memory deficits caused by GBA mutation. Thus, as discussed in our Annals Neurology paper (Cullen et al., 2011), and as demonstrated by Sardi et al., increasing the brain's GBA content may be a viable therapeutic strategy to explore further. Perhaps eventually, a combination approach may be used, with GBA expression utilized to combat loss of enzyme function, and GBA chaperoning and/or lysosomal support (see, e.g., our results with isofagomine and rapamycin) utilized to combat a gain of toxic function of mutant GBA.


    . Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. Mol Genet Metab. 2011 Apr;102(4):436-47. PubMed.

    . Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. Ann Neurol. 2011 Jun;69(6):940-53. PubMed.

  3. The paper by Sardi et al., 2011, provides further important in-vivo evidence of a mechanistic link between Gaucher’s disease and α-synuclein processing. The demonstration that accumulation of α-synuclein and behavioral deficits in Gaucher's disease mice can be ameliorated by increasing glucocerebrosidase levels suggests that this lysosomal enzyme may be an important therapeutic target for the treatment of synucleinopathies. It will be of future interest to determine whether enhancing glucocerebrosidase function, either through adenoviral-mediated glucocerebrosidase expression or administration of pharmacological chaperones, has the ability to reverse or clear the accumulation of α-synuclein in aged (12-month-old) Gaucher's mice that are symptomatic.

    The recent exciting paper by Lim et al. (Lim et al., 2011), which demonstrates that behavioral deficits and pathology induced by α-synuclein overexpression can be reversed, suggests that methods that enhance the clearance of α-synuclein may provide therapeutic benefit even after symptoms are apparent. Augmentation of glucocerebrosidase function appears to be one such option that may accelerate the clearance of α-synuclein and prevent further disease progression in Parkinson's disease and other synucleinopathies.


    . 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.