Cu, Zn-superoxide dismutase 1 (SOD1) is a novel target of Puromycin-sensitive aminopeptidase (PSA/NPEPPS): PSA/NPEPPS is a possible modifier of amyotrophic lateral sclerosis
© Ren et al; licensee BioMed Central Ltd. 2011
Received: 25 January 2011
Accepted: 7 May 2011
Published: 7 May 2011
Accumulation of misfolded neurotoxic Cu, Zn-superoxide dismutase-1 (SOD1) protein found in both familial and sporadic amyotrophic lateral sclerosis (ALS) is recognized as an important contributing factor of neuronal cell death. However, little is known about the mechanisms controlling the accumulation and turnover of SOD1 protein. Puromycin-sensitive aminopeptidase (PSA/NPEPPS) was recently identified as a major peptidase acting on neurotoxic TAU protein and protecting against TAU-induced neurodegeneration. In addition, recent report implicated PSA/NPEPPS in the direct removal of neurotoxic polyglutamine repeats. These combined data suggest that PSA/NPEPPS might represent a novel degradation pathway targeting pathologically aggregating neurotoxic protein substrates including SOD1. Here, we report that PSA/NPEPPS directly regulates SOD1 protein abundance and clearance via proteolysis. In addition, PSA/NPEPPS expression is significantly decreased in motor neurons of both SOD G93A transgenic mice and sporadic ALS patients, suggesting its possible contribution to the disease pathogenesis. These results implicate SOD1 as a new target protein of PSA/NPEPPS and point to the possible neuroprotective role of PSA/NPEPPS in ALS.
Familial amyotrophic lateral sclerosis (FALS) represents about 10% of ALS cases. It is most frequently inherited as an autosomal dominant trait . In about 20% of FALS patients, at least one type of mutation in Cu, Zn-superoxide dismutase-1 (SOD1) can be found . The ubiquitous SOD1 protein converts superoxide radical anions to oxygen and hydrogen peroxide. More than a hundred SOD1 gain-of-function mutations have been identified, which may contribute to increased oxidative stress, altered copper metabolism, protein aggregation, excitotoxicity, or altered axonal transport . Several other genes, including alsin, senataxin, vesicle-associated membrane protein-associated protein B, angiogenin, and TAR DNA binding protein, have also been found to be associated with ALS [4, 5]. However, about 90% of ALS cases have no clear genetic cause, and the condition is referred to as sporadic amyotrophic lateral sclerosis (SALS) .
One of the hypotheses explaining selective motor neuron degeneration in ALS is the toxicity of intracellular protein aggregates. One of the major protein aggregates commonly found in FALS is the misfolded SOD1 protein [6–8]. Not surprisingly, aggregates of mutated SOD1 protein are found in neurons and astrocytes of SOD1 transgenic animals, including G37R, G85R and G93A models, and the degree of SOD1 accumulation strongly correlates with motor neuron dysfunction . Immunohistochemical studies have also localized these inclusions predominantly to motor neurons, and in some cases, astrocytes . Wild-type misfolded SOD1 is also found in the spinal cord extracts of SALS patients and may play a role in the etiology of SALS [6, 11, 12].
Accumulation of abnormally folded proteins and peptides is a key feature of many neurodegenerative diseases, including Alzheimer's disease, Huntington's disease and ALS [13–16]. The presence of misfolded SOD1 protein in both familial and sporadic ALS presents a credible explanation of motor neuron specific death in ALS [6, 8, 11, 12, 17–19]. Recent work convincingly demonstrated that wild-type SOD1 and mutant SOD1 share a conformational epitope prone to oxidation and therefore exert a strong neurotoxic effect [11, 12, 20]. These data strongly support the hypothesis that either mutated or wild-type SOD1 misfolding contributes to disease pathogenesis in both familial and sporadic ALS. Recent studies describing RNAi based allele-specific silencing of mutant SOD1 convincingly demonstrated that lowering the levels of mutant SOD1 protein produces a significant therapeutic benefit in SOD1G93A mice . This shows that targeting SOD1 is a viable and important therapeutic strategy for which identification and characterization of mechanisms controlling SOD1 protein degradation would play a central role. Unfortunately, the causes of SOD1 misfolding/accumulation, and more importantly, the mechanisms of the clearance of pathological aggregates remain unclear, which may very well be a valid target of novel therapeutic approaches for ALS.
Recently, we have identified puromycin-sensitive aminopeptidase (PSA, also known as NPEPPS) as a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein [22, 23], which was later confirmed by others . Another recent report implicated PSA as the major peptidase digesting polyglutamine sequences in Huntington's disease . In addition, it was recently hypothesized that neuroprotective effect of PSA/NPEPPS may be linked to the autophagy system and several other neurotoxic targets in vitro, including polyQ-expanded huntingtin exon-1, ataxin-3, mutant α-synuclein, and SOD1 . These results suggest that PSA/NPEPPS may represent a universal neuroprotective mechanism acting on pathologically aggregating neurotoxic proteins substrates, including SOD1. However, the questions whether PSA/NPEPPS is capable of removing SOD1 protein directly through its proteolytic activity and whether it contributes to the pathogenesis of familial and sporadic ALS remain unanswered.
Here, we investigated the role of PSA/NPEPPS in SOD1 protein clearance in vitro in cell culture and cell-free systems and evaluated the levels of PSA/NPEPPS in both human postmortem SALS motor neurons and murine ALS model tissues.
Moreover, we also studied whether overexpression of SOD1 affects the expression of endogenous PSA/NPEPPS. In mouse neuroblastoma cell line N1E-115 transfected with mouse SOD1 overexpression vectors pCMV6-XL-SOD1, mouse PSA/NPEPPS protein expression was upregulated up to 4-fold (p = 0.0001) (Figure 1C). Thus, it seems that PSA/NPEPPS expression is directly proportional to the levels of SOD1 protein and the elevation of SOD1 leads to significant increase in PSA/NPEPPS protein expression. These observations taken together suggest that PSA/NPEPPS is indeed a direct endogenous regulator of SOD1 protein abundance and its expression is controlled in response to alterations of intracellular SOD1 levels through a positive feed-back mechanism. A similar regulation of PSA expression has been reported in PC12 cells that overexpress hungingtin exon 1 containing polyQ sequences, in which PSA/NPEPPS expression is highly induced . These results suggest that there may be a feed-back self-protective mechanism in cells by which PSA/NPEPPS expression is regulated in response to the abundance of aggregated toxic proteins. This further implies the important physiological neuroprotective role of PSA/NPEPPS.
Using human neuroblastoma SH-SY5Y cells we demonstrated a strong linkage of PSA/NPEPPS to SOD1 accumulation/clearance (Figure 1A and 1B). This effect may be mediated by direct interaction of PSA/NPEPPS with SOD1 resulting in SOD1 protein digestion similar to PSA/NPEPPS interaction with TAU-protein [22, 23]. However, it is plausible that PSA/NPEPPS has no direct interaction with SOD1, and acts via cleavage of another intermediary, such as the autophagy system  or ptoteosome system . Our recent studies of hPSA transgenic mice overexpressing human PSA/NPEPPS at nearly 3-fold revealed that it has no significant effect on either autophagy or proteosome degradation system . Nevertheless, to test the hypothesis that human PSA/NPEPPS can act directly on human SOD1 two types of experiments were performed in the cell-free system using purified SOD1 and PSA/NPEPPS proteins.
Although post-microsomal protein fractions are free of autophagosomal vesicles, other cytoplasmic peptidases may contribute to SOD1 degradation process . To further confirm that PSA/NPEPPS indeed acts on SOD1 protein directly and is capable of degrading it, we incubated purified human SOD1 with well-purified PSA/NPEPPS in a cell-free system. PSA/NPEPPS was purified from brains of adult male Sprague-Dawley rats (250-300 g) and its activity was measured with 20 μM Leu βNA (Leu-naphthylamide) as described previously . For PSA-SOD1 incubation experiments, digestion of highly purified human SOD1 (Sigma-Aldrich, MO) was carried out at 37°C for 6 hrs in 50 mM Bicine buffer, pH 7.0, containing 0.2 mM DTT, at a molar ratio of 1:6 (PSA:SOD1). The reaction was terminated by 5% perchloroacetic acid and analyzed by Western blot as described above. After 6 hours of incubation, full-length SOD1 was greatly diminished of its original amount (about 80% decrease, p = 0.004) (Figure 2B). These results further strengthen the hypothesis of PSA/NPEPPS-specific SOD1 degradation through its direct proteolytic activity similar to the effect of PSA/NPEPPS on TAU-protein [22, 23]. Moreover, our studies with post-microsomal protein fractions showed that such protein fractions even from cells that lack PSA/NPEPPS expression are also capable of digesting SOD1 protein at a low rate, which suggests that there may be other unknown PSA-independent mechanisms responsible for SOD1 hydrolysis, which remain to be verified in the future. Based on observations made by us and by others , PSA/NPEPPS may regulate SOD1 degradation through both direct (i.e. its proteolytic activity) and indirect (such as autophagy system involved) mechanisms. Our findings indicate that SOD1 protein may be removed directly through the increased activity of PSA/NPEPPS, and implicate this enzyme as an important modulator of SOD1-induced motor neuron degeneration in ALS.
Although the presence of misfolded SOD1 in the motor neurons of sporadic ALS patients is still a debated topic evidenced by several contradicting reports [6, 8, 11, 12, 17–19, 35, 36], recently published data points to the importance of SOD1 in the pathogenesis of the sporadic disease . It was demonstrated that oxidized wild-type SOD1 shares similar structural and neurotoxic features with mutated SOD1. It appears that SOD1 oxidation process leads to specific conformational changes in SOD1 creating an epitope identical to mutated and neurotoxic SOD1 . In over 50% of SALS patients such aberrant wild-type SOD1 are detected, and SOD1 extracted from tissue samples of SALS patients, but not SOD1 from healthy controls, inhibited axonal transport, pointing to its strong neurodegenerative potential . These results suggest that abnormal conformations of oxidized wild-type SOD1 could indeed mediate motor neuron toxicity in SALS similar to the role of mutated SOD1 in FALS .
We then studied whether PSA/NPEPPS expression was altered in SALS patients. Post-mortem paraffin-embedded clinically relevant brain and spinal cord tissue blocks from SALS patients (n = 19) and normal controls (n = 6) were provided by the UCLA Department of Pathology and the National Neurological AIDS BANK (NNAB), and used for tissue microarray (TMA) construction at the UCLA Tissue Array core facility (http://www.genetics.ucla.edu/tissuearray) as described previously . Estimation of PSA/NPEPPS expression was performed in spinal cord anterior horn motor neurons of SALS and control subjects. Briefly, for the estimation of relative PSA/NPEPPS expression, the total number of PSA/NPEPPS positive motor neurons was divided by the total number of NeuN positive motor neurons to derive the PSA expression index (PEI) for a given tissue core. Then, the average PEI for each tissue type and individual was calculated and used to derive the mean PEI for SALS and control subjects. The significance was estimated based on a Student's t-test (P < 0.01). The following primary antibodies were used: mouse monoclonal anti-neuronal nuclei (NeuN; 1:100; Chemicon) and goat polyclonal anti-PSA (1:1000, Millipore). This high-throughput immunohistochemical analysis of TMA showed a significant decrease of PSA/NPEPPS protein expression in the SALS motor neurons (p = 0.0013, Figure 3C and 3D). For the first time, we demonstrated that decreased expression of PSA/NPEPPS may be a novel contributory factor to the pathogenesis of ALS, which leads to the impaired clearance of accumulated SOD1.
Our in vitro results with murine neuroblastoma cell line overexpressing SOD1 demonstrated an increase in PSA/NPEPPS protein expression (Figure 1C). However, the evidence in vivo show that the levels of PSA/NPEPPS protein are dramatically decreased in the transgenic mice overexpressing mutated (G93A) form of human SOD1 and in postmortem spinal cord tissues, more specifically motor neurons, of SALS patients (Figure 3). Two possible mechanisms may explain these conflicting observations in vitro and in vivo: 1. the rapid upregulation of PSA/NPEPPS is just the early-response to elevated intracellular SOD1; however, the prolonged and constitutive elevation of SOD1 eventually leads to the decreased expression of PSA/NPEPPS; 2. In SALS disease, the physiological feed-back regulatory mechanism of PSA/NPEPPS expression in response to SOD1 levels is impaired. The latter may represent a novel angle of view of ALS pathogenesis. Future studies of the interaction of PSA/NPEPPS with SOD1 would be prerequisite to understand its biological mechanisms. In particular, the cross between recently developed hPSA transgenic mice  and SOD1 G93A mice  with subsequent analysis of double transgenic progeny in respect to SOD1 G93A protein accumulation would be valuable. Further cell free co-incubation experiments using mutated forms of SOD1 would provide additional information on the specificity of interaction with PSA/NPEPPS. These and other experiments would shed new light on the role of PSA/NPEPPS in the pathogenesis of ALS and may provide novel therapeutic and diagnostic approaches for ALS.
In summary, we present the first evidence that PSA/NPEPPS is a major protease to directly digest SOD1, which may be analogous to its role in TAU-induced neurodegeneration [22–24]. More importantly, its expression is attenuated in both murine ALS model and SALS patients, which suggests its potential contribution to ALS pathogenesis. However, additional functional and etiological studies are needed to fully evaluate the role of PSA/NPEPPS in ALS and its possible use as a therapeutic target facilitating SOD1 protein clearance.
amyotrophic lateral sclerosis
familial amyotrophic lateral sclerosis
sporadic amyotrophic lateral sclerosis
Cu, Zn-superoxide dismutase-1
Acknowledgements and Funding
The work was supported by the RGK Foundation (S.L.K.).
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