5th Conference on Advances in Molecular Mechanisms Underlying Neurological Disorders

Emerging insights into the mechanistic link between α-synuclein and glucocerebrosidase in Parkinson’s disease Ryan P. McGlinchey* and Jennifer C. Lee*1 *Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.

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Abstract Mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase, cause the lysosomal storage disorder GD (Gaucher’s disease), and are associated with the development of PD (Parkinson’s disease) and other Lewy body disorders. Interestingly, GBA1 variants are the most common genetic risk factor associated with PD. Although clinical studies argue a strong case towards a link between GBA1 mutations and the development of PD, mechanistic insights have been lacking. In the present article, we review recent findings that have provided some biochemical evidence to bridge this relationship, focusing on the molecular link between two proteins, α-synuclein and glucocerebrosidase, involved in PD and GD respectively.

Introduction GCase (glucocerebrosidase), a 497-residue lysosomal hydrolase, cleaves the β-glucosyl linkage of GlcCer (glucosylceramide) to glucose and ceramide [1]. To date, over 300 mutations (point mutations, deletions, insertions, etc.) have been identified that result in the loss of GCase activity, by insufficient protein translation, protein misfolding or incorrect trafficking to the lysosome, resulting in the build-up of the substrate GlcCer [2,3]. The relationship between the type of mutation in GCase and the clinical phenotypes are unclear. Clinical observations reveal three types of GD (Gaucher’s disease): non-neuronopathic (type 1), the most common, and neuronopathic (types 2 and 3) disease [1]. In non-neuronopathic cases, most organs and tissues are affected, whereas in neuronopathic types, the nervous system is implicated. The type and symptoms can vary widely among individuals ranging from enlarged liver and spleen to brain problems such as seizures and dementia. Enzyme-replacement therapy involving periodic administration of recombinant GCase is the only effective treatment in type 1 patients [4]. PD (Parkinson’s disease) is an age-related degenerative disorder of the central nervous system that results in neuron death causing symptoms such as tremor, stiffness, slowness and difficulty with posture [5]. One hallmark of the disease is the presence of cytoplasmic inclusions called LBs (Lewy bodies), enriched in insoluble fibrillar α-syn (α-synuclein) aggregates and lipid deposits that develop in surviving neurons [6,7]. Five missense α-syn mutations, A30P, E46K, H50Q, G51D and A53T [8–12], and gene duplications or

Key words: amyloid, Gaucher disease, glucocerebrosidase, lysosome, Parkinson’s disease, α-synuclein. Abbreviations used: CatD, cathepsin D; CBE, conduritol β-epoxide; ER, endoplasmic reticulum; GCase, glucocerebrosidase; Gaucher’s disease; GlcCer, glucosylceramide; LB, Lewy body; LIMP-2, lysosomal integral membrane protein type-2; PD, Parkinson’s disease; SapC, saposin C; SN, substantia nigra; α-syn, α-synuclein. 1 To whom correspondence should be addressed (email [email protected]).

Biochem. Soc. Trans. (2013) 41, 1509–1512; doi:10.1042/BST20130158

triplications [13,14] are strongly associated with early-onset PD, although the specific pathogenic role of α-syn remains to be determined. Recent clinical and genetic studies now point to a new association between mutations in the GBA1 gene and the development of PD [15–17]. Since α-syn is predominantly degraded by lysosomes, in part by chaperonemediated autophagy [18], and GCase is a lysosome hydrolase, a connection between these two proteins and their associated diseases is intriguing.

Relationship between α-syn and GCase The relevance of GD to PD comes from the observation that GD patients and heterozygous GBA1 mutation carriers are at an increased risk of developing PD [19]. In fact, clinical studies have shown that PD patients are over five times more likely to carry a mutation in the GBA1 gene [15]. Conversely, GD and GBA1 mutation carriers have an increased risk of developing PD, although the vast majority of such individuals do not get the disease. Post-mortem analysis of GD-affected individuals and carriers with PD symptoms harbour LBs enriched with mutant GCase and α-syn [20]. Moreover, GBA1 carriers had more cortical LBs compared with those without mutations. Analysis of PD brains with GBA1 mutations showed a significant reduction in GCase activity in the SN (substantia nigra), a site with greatest neurodegeneration in PD [21]. This reduction in activity was also accompanied by a decreased level of GCase. Interestingly, GCase activity was also reduced in the SN of individuals with sporadic PD [21]. On the basis of clinical and genetic evidence, two models have been proposed for the observed association, a GBA1 mutant mediated loss-of-function and a toxic gainof-function. Several GBA mutants (e.g. N370S and L444P) overexpressed in neuronal cells displayed elevated levels of endogenous α-syn in a time- and dose-dependent manner [22]. Here, the levels of α-syn did not correlate with GCase enzyme activity, but were dependent on the amount of  C The

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transfected mutant cDNA and protein synthesized [22]. These data would imply a toxic gain-of-function mechanism, which is independent of GCase activity. In contrast, wildtype GCase knockdown experiments in primary neurons using shRNA by lentiviral infection caused a dramatic increase in the levels of oligomeric α-syn [23]. Furthermore, enzymatic inhibition of GCase by CBE (conduritol βepoxide) in human dopaminergic cells and the SN of mice revealed elevated levels of α-syn, supporting a loss-offunction mechanism [24,24a]. However, this observation has been disputed, since treatment of CBE in another in vivo model does not increase α-syn protein levels [25]. Several GD mouse models that have mutants identical with those found in humans have been studied to look at the effect on α-syn levels and pathology [26]. Interestingly, a heterozygous Gaucher (D409V) mouse displaying a ∼50% reduction in GCase activity showed accumulation of α-syn aggregates, but, more importantly, no change in substrate levels in the brain were apparent, implying a toxic gain-of-function [27]. This result is analogous to human carriers of heterozygous GBA1 mutations that show no consistent evidence of substrate accumulation. On the basis of tissue culture and animal models, it is conceivable that either mechanism plays a role in PD susceptibility, or in combination may exert a more pronounced age-related effect. Studies demonstrating a reciprocal relationship between GCase and α-syn have paved the way in finding treatments for both GD and GBA1 mutation carriers with PD. Interests outside of enzyme-replacement therapy have been strategies to increase GCase trafficking and activity. For example, it was demonstrated recently that viral vector-mediated increase in wild-type GCase levels can reverse PD-related features in a GD mouse model [28,29]. Here, GCase delivery into the brains of mice reduces the accumulation of both substrate and α-syn. Furthermore, overexpression of GCase in A53T α-syn mice reduced the levels of α-syn. These studies suggest that enhancing GCase activity is a potential therapeutic strategy for synucleinopathies with or without GBA1 mutations. Other strategies include small-molecule chaperones such as ambroxol [30] and isofagomine [31]. These competitive inhibitors of GCase bind to the misfolded protein, correcting folding to permit passage through the ER (endoplasmic reticulum) to the lysosome. A more recent study highlights a new class of non-inhibitory chaperones, pyrazolopyrimidines [32], which were shown to offer an advantage over all other small-molecule chaperones in not inhibiting GCase activity. Another complimentary strategy is the use of histone deacetylase inhibitors, which are known to affect the heat-shock gene response by limiting the deacetylation of the chaperone HSP90 (heat-shock protein 90), causing a reduced recognition of misfolded mutant GCase [33,34].

Mechanistic insights into GBA1-associated PD A mechanistic link between GBA1 mutations and α-syn has been the subject of recent investigations, which have  C The

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provided some new perspectives. One possible scenario is that misfolded and accumulated GCase leads to insufficient α-syn degradation by either disrupting the ubiquitin–proteasomal pathway or causing impairment of lysosome function, resulting in α-syn aggregation. Alternatively, misfolded GCase is degraded, leading to loss of enzyme activity and build-up of substrate, influencing lipid homoeostasis. This, in turn, could lead to disruption of α-syn membrane binding and enhance aggregation. Although both scenarios have gained community support, each has its own pitfalls. For example, some PD patients have GBA1-null mutations, a finding in conflict with a gain-of-function mechanism. A strong argument against loss-of-function is that most GD patients do not get PD, despite having low levels of GCase. One study discovered that a physical interaction existed between recombinant α-syn and GCase under lysosomelike conditions [35]. Here, fluorescently labelled α-syn at the C-terminus (residue 136), when co-incubated with GCase at pH 5.5, showed significant spectral changes, indicating binding of the C-terminal region of α-syn to GCase. Dissociation constants ranging from 1 to 20 μM were reported where protein–enzyme complex formation is modulated by the ionic strength of the solution. This interaction was abolished under physiological buffer conditions of pH 7.4. NMR spectroscopy revealed residues 118–137 of α-syn as being the site of GCase interaction. Immunoprecipitation results of brain samples taken from PD patients showed endogenous GCase and α-syn coimmunoprecipitated at pH 5.5, but not at 7.4, in accord with fluorescence and NMR data obtained from recombinant proteins. Additionally, immunofluorescence imaging of neuronal cells overexpressing GCase and α-syn showed co-localization of the proteins in the lysosome. These compelling results offer new mechanistic insights into the connection between these two proteins, where one could envisage an interaction that has a beneficial consequence under normal physiological conditions (Figure 1). A further extension to these findings showed that a common GDrelated mutant, N370S, which has reduced enzymatic activity, had reduced affinity for α-syn, suggesting that a weakened interaction could perturb the system, thereby promoting αsyn accumulation (Figure 1). A follow-up study extended this physical interaction by considering how membranes would influence the α-syn– GCase complex, since membranes are pertinent for both enzyme activity and α-syn conformation [36,37]. Here, comparable affinities were shown between the two proteins on and off the membrane; however, when membraneassociated, this physical interaction involved a larger α-syn region. This shift included residues that were N-terminal to the binding region seen in membrane-free solution. Interestingly, α-syn was shown to act as a potent GCase inhibitor only when membrane-bound, adopting an α-helical structure, with a reported IC50 in the submicromolar range. This observation offers a mechanistic extension into the physical connection of these two proteins. Mutations that decrease GCase levels or weaken the α-syn interaction would

5th Conference on Advances in Molecular Mechanisms Underlying Neurological Disorders

Figure 1 Proposed molecular links between α-syn and GCase In normal functioning lysosomes (left, green), wild-type GCase (purple) enters the lysosome via vesicle transport from the ER/Golgi apparatus. α-Syn is trafficked to the lysosome by CMA (chaperone-mediated autophagy) and translocated across the membrane. Upon lysosomal entry, GCase hydrolyses the substrate GlcCer (open white circles), on intralysosomal vesicles, whereas α-syn is targeted for proteolytic degradation. At the same time, an α-syn–GCase complex may form, a result of the physical interaction of the C-terminal domain of α-syn and GCase. This interaction could have a beneficial effect by promoting lysosomal degradation of α-syn, or inhibiting its aggregation propensity. In compromised lysosomes (right, yellow) with mutant GBA1 (blue), several scenarios may occur. GCase mutations (blue), resulting in its decrease in activity or levels, cause the build-up of GlcCer (note more open circles) on intralysosomal vesicles, which in turn accelerate and stabilize α-syn aggregates en route to fibril formation. Here, one might infer that this type of mechanism could limit α-syn degradation, whereas stabilized oligomers compromise the integrity of the lysosome. Additionally, α-syn could accumulate in the ER/Golgi and block the trafficking of residual GCase that might otherwise reach the lysosome (not shown). This in turn would exacerbate the situation by further increasing substrate levels and stabilizing α-syn oligomers, resulting in further inhibition of GCase trafficking. Alternatively, the build-up of intralysosomal vesicles and α-syn could strengthen a membrane-bound GCase–α-syn interaction, which would have an inhibitory effect on residual GCase, resulting in further loss of activity.

increase the levels of α-syn and GlcCer and thereby may facilitate α-syn–GCase complex formation on the membrane, which would in turn lead to a secondary loss in GCase activity through α-syn inhibition (Figure 1). Whereas this physical interaction offers a new perspective, other pathological factors are likely to be involved, since only a small fraction of GD patients and carriers develop PD. A different mechanistic connection between these two proteins was reported recently [23]. Here, it was shown that depletion of enzyme in primary cultures and human iPS (induced pluripotent stem) neurons compromised lysosomal protein degradation, leading to an increase in α-syn aggregation levels. Biochemical analysis revealed an increase in oligomeric α-syn in GCase-depleted neurons, suggesting that this may be a fundamental consequence of GBA1

mutations. In vitro analysis using recombinant monomeric α-syn showed that GlcCer affected its aggregation propensity, causing a prolonged lag phase of fibril growth only at acidic pH. Although ill-defined in this study [23], the authors speculate that, under these conditions, pre-fibrillar oligomeric species are stabilized, which in turn may be an important step in the pathology of the disease (Figure 1). In addition, it was shown that overexpressing α-syn inhibits intracellular trafficking and lysosomal activity of endogenous GCase in neurons. These data imply that decreased wild-type GCase activity may influence the development of sporadic synucleinopathies. Collectively, the authors proposed a positive-feedback loop mechanism where GCase depletion in the lysosome causes build-up of the substrate GlcCer, which in turn stabilizes formation of toxic α-syn oligomers [23]. The buildup of α-syn further blocks the ER–Golgi trafficking of GCase, leading to further GlcCer accumulation and α-syn aggregation (Figure 1).

Concluding remarks Although mechanistic insights are emerging into the connection between α-syn and GCase dysfunction, further data are warranted to support or refute these notions. Furthermore, it is known that other lysosomal proteins such as LIMP-2 (lysosomal integral membrane protein type-2) [38,39] and SapC (saposin C) [40], which were not discussed above, play a role in GCase trafficking and enzymatic activity respectively. For example, SapC, an essential activator for the hydrolysis of GlcCer by GCase in lysosomes, is believed to physically associate with both GCase and the phospholipid membrane [40]. Interestingly, SapC levels are increased in the spleens of patients with GD, possibly to compensate for loss in GCase protein levels by raising residual GCase activity. Furthermore, SapC deficiency produces clinical phenotypes similar to GD, despite normal GCase levels [40]. As for LIMP-2, which is a specific binding partner of GCase, transporting it to the lysosome from the trans-Golgi network, mutations in the gene are implicated in myoclonic epilepsy which is part of the GD phenotypic variation [38,41]. On a final note, the protease CatD (cathepsin D) has been identified as the main lysosomal enzyme to degrade α-syn [42], resulting in C-terminal truncations that have been identified in isolated lysosomes [42]. One might therefore speculate that up-regulating CatD may alleviate some of the symptoms associated with PD and other synucleinopathies. These data imply that all three proteins should be considered as modifiers in GD and PD. Particularly, the interplay between them may be important, as patients with identical GBA1 mutations display different phenotypes. Clearly, future investigations are needed to evaluate their roles in GD and PD progression.

Funding This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health.

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Received 23 July 2013 doi:10.1042/BST20130158

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Emerging insights into the mechanistic link between α-synuclein and glucocerebrosidase in Parkinson's disease.

Mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase, cause the lysosomal storage disorder GD (Gaucher's disease), and are associated wi...
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