Neurochemistry International 69 (2014) 1–8

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Revisiting the neuropathogenesis of Zellweger syndrome Denis I. Crane ⇑ Eskitis Institute for Drug Discovery, and School of Biomolecular and Physical Sciences, Griffith University, Qld, Australia

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Article history: Received 18 December 2013 Received in revised form 11 February 2014 Accepted 24 February 2014 Available online 6 March 2014 Keywords: Zellweger syndrome Neuropathogenesis Neurodevelopment Neurodegeneration Peroxisome

a b s t r a c t Zellweger syndrome (ZS) is a neonatal-lethal genetic disease that affects all tissues, and features neuropathology that involves primary developmental defects as well as neurodegeneration. Neuropathological changes include abnormal neuronal migration affecting the cerebral hemispheres, cerebellum and inferior olivary complex, abnormal Purkinje cell arborisation, demyelination and post-developmental neuronal degeneration. ZS is caused by mutations in peroxisome biogenesis, or PEX, genes which lead to defective peroxisome biogenesis and the resultant loss of peroxisomal metabolic function. The molecular and cellular bases of ZS neuropathology are still not completely understood. Attempts to explain the neuropathogenesis have implicated peroxisomal metabolic dysfunction, and more specifically the loss of peroxisomal products, such as plasmalogens and docosahexaenoic, and the accumulation of peroxisomal substrates, such as very-long-chain-fatty acids. In this review, consideration is also given to recent findings that implicate other candidate pathogenetic factors, such as mitochondrial dysfunction, oxidative stress, protein misfolding, aberrant cell signalling, and inflammation – factors that have also been identified as important in the pathogenesis of other neurological diseases. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Zellweger syndrome (ZS) is the prototypical member of the peroxisome biogenesis disorders (PBDs), a group of disorders with significant neurological involvement that result from defective biogenesis of the peroxisome (Moser, 1993). Of the wider group of diseases comprising the PBDs, ZS, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) represent a clinical continuum, referred to as the Zellweger (syndrome) spectrum, with ZS the most severe, and IRD the least severe. Patients with ZS rarely survive their first year, whereas IRD patients may survive beyond their third decade. PBDs are inherited in an autosomal recessive manner through mutations in PEX genes that encode proteins, termed peroxins, required for the normal biogenesis of the peroxisome (Distel et al., 1996; Gould and Valle, 2000). At the molecular level, mutations in most peroxins disrupt the molecular apparatus required for post-translational import into the peroxisome of matrix proteins containing either a peroxisomal targeting signal (PTS) 1 or 2. A number of other peroxins are required for the delivery of proteins to the peroxisomal membrane and mutations in these peroxins disrupt peroxisomal membrane formation and indirectly prevent

⇑ Address: School of Biomolecular and Physical Sciences, Griffith University, Nathan, Qld 411, Australia. Tel.: +61 (7)37357253; fax: +61 (7)37357773. E-mail address: d.crane@griffith.edu.au http://dx.doi.org/10.1016/j.neuint.2014.02.007 0197-0186/Ó 2014 Elsevier Ltd. All rights reserved.

matrix protein import. The Zellweger spectrum diseases result from defects in peroxins required for membrane protein import, PTS1 protein import alone, or both PTS1 and PTS2 protein import (Sacksteder and Gould, 2000; Subramani et al., 2000; Purdue and Lazarow, 2001). Disease severity is related to the nature of the PEX gene mutation and the resulting impact on the function of the affected peroxin (Crane et al., 2005; Steinberg et al., 2006). Another clinical phenotype, classical rhizomelic chondrodysplasia punctata (RCDP), is distinct from the ZS spectrum in terms of genetics and phenotype, and is caused by defects in the import of matrix proteins with a PTS2 (Braverman et al., 1997). Peroxisomes are required for a number of essential metabolic functions, including the b-oxidation of very long chain fatty acids (VLCFA), phytanic acid oxidation and the synthesis of docosahexaenoic acid, bile acids and plasmalogens (Schutgens et al., 1986; Gould et al., 2001). ZS is thus characterised by the absence or deficiency of normal peroxisomes and loss of this organelle’s usual complement of proteins and metabolic pathways. 2. ZS clinical features ZS manifests with a wide range of clinical features that indicate primary developmental defects, including dysmorphia, psychomotor delay, neonatal seizures, hepatomegaly, renal cysts, retinopathy, adrenal insufficiency, skeletal abnormalities, cataracts and impaired hearing (Volpe and Adams, 1972; Moser, 1993; Weller

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et al., 2003). The neurological abnormalities are pronounced and include abnormal neuronal migration affecting the cerebral hemispheres, cerebellum and inferior olivary complex, abnormal Purkinje cell arborisation, and abnormal white matter (demyelination, dysmyelination or hypomyelination). In addition, there is evidence of post-developmental neuronal degeneration (Powers et al., 1989; Powers and Moser, 1998).

cases point to a multi-factorial cause of brain pathology that may require more than just isolated peroxisomal metabolic dysfunction. In response to these challenges, mouse models of ZS have been developed to provide systems that are more amenable to experimental manipulation and analysis.

4. Mouse models of ZS 3. Etiology of ZS: theories coupled to peroxisomal metabolic dysfunction Peroxisomes play an important metabolic role in brain (Trompier et al., 2013), peroxisome abundance is greater in the developing brain (Ahlemeyer et al., 2007), and peroxisomal dysfunction in the developing brain has severe neuropathological consequences (Barry and O’Keeffe, 2013). However, our understanding of the multiorgan abnormalities of ZS and the links between the cellular mechanisms and disease pathogenesis is still incomplete. The loss of peroxisomal function that occurs in ZS represents an obvious general metabolic failure that may be expected to underpin pathogenesis. A number of individual pathogenetic factors have therefore been implicated based on deficient peroxisomal metabolic pathways and the accumulation of potentially toxic peroxisomal metabolic substrates on one hand, and/or the deficiency of peroxisomal synthetic products on the other. Peroxisomes are responsible for the b-oxidation of very-longchain-fatty acids (VLCFA) (Lazarow and De Duve, 1976; Lazarow, 1978), which includes a pathway for the generation of docosahexaenoic acid (DHA), a major brain polyunsaturated fatty acid. Peroxisomal b-oxidation also encompasses the metabolism of polyunsaturated fatty acids (PUFA) and their eicosanoid and docasanoid derivatives, and branched fatty acids and dicarboxylic acids (Wanders, 2004; Trompier et al., 2013). In addition, peroxisomal enzymes catalyse steps in the synthesis of ether-lipids, of which plasmalogens are the most abundant class (Schutgens et al., 1986; Wanders, 2004). Candidate pathogenetic factors for brain pathology have therefore included elevated VLCFA or other fatty acid substrates or metabolites, and deficient plasmalogens and DHA (Moser, 1993; Powers and Moser, 1998), or combinations of these factors. VLCFA have long been considered as a possible factor contributing to brain pathogenesis, esp. the abnormal neuronal migration, given the high levels of VLCFA in ZS brains and the proposed cellular toxicity of these fatty acids (Powers and Moser, 1998). However VLCFA alone are unlikely to account for all neuropathology; for example patients with the X-linked form of adrenoleukodystrophy (X-ALD), where the hallmark biochemical abnormality is elevated brain VLCFA, show no evidence of abnormal neuronal migration (Ferrer et al., 2010; Singh and Pujol, 2010; Trompier et al., 2013). In addition, mouse models of ZS (see Section 4) cast further doubt on an isolated role of VLCFA in neuropathogenesis. Loss of plasmalogens is considered a strong pathogenetic factor in ZS, especially because of their proposed anti-oxidative stress function in brain (Zoeller et al., 1988; Wallner and Schmitz, 2011). However, the primary involvement of plasmalogen deficiency in aspects of ZS pathogenesis is confounded by the absence of neuronal migration defects in RCDP patients, who have a specific defect in plasmalogen synthesis (Braverman et al., 1997; Barry and O’Keeffe, 2013). DHA dietary supplementation of patients has been trialled, but with mixed results, with earlier findings on a small number of patents suggesting clinical improvement (Martinez et al., 1993), but a later randomized trial indicating no beneficial effect (Paker et al., 2010). In general, findings from investigations of ZS patients have allowed a snapshot of the neuropathology without providing a satisfactory understanding of the underlying mechanisms, and in many

Several research groups have developed mouse models of ZS based on inactivation of PEX genes, which leads to generalized loss of peroxisomal metabolism. Other studies have targeted genes encoding enzymes/proteins of peroxisomal b-oxidation pathway, ether-lipid (plasmalogen) synthesis, or other peroxisomal metabolic pathways in order to isolate key pathway-specific pathology. These animal models have been informative in testing a number of hypotheses on the pathogenesis of ZS. Three mouse models of ZS, generated through targeted disruption of the PEX2 (Faust and Hatten, 1997), PEX5 (Baes et al., 1997) and PEX13 (Maxwell et al., 2003) genes, have been developed. Pups from all three null strains exhibit biochemical abnormalities typical of ZS and display many of the same clinical features and tissue changes, including neonatal lethality, intrauterine growth retardation, hypotonia, developmental delay and impaired neuronal migration and maturation of the neocortex. Mice with brain-specific deficiency of PEX5 (Krysko et al., 2007) show defects in cortical neuronal migration and delayed formation of the cerebellum, and mice with brain-specific deficiency of PEX13 show a similar delay in cerebellum formation (Muller et al., 2011). These findings are compatible with an intrinsic role of brain peroxisomes in brain development. Nevertheless, the involvement of both brain and extra-neural factors in brain development in peroxisome-deficient mice has been recognized (Faust et al., 2005). Indeed, direct tissue gene-rescue experiments have indicated a combined role for brain and liver peroxisomes in the neuronal migration process (Janssen et al., 2003) and cerebellum maturation (Janssen et al., 2003; Krysko et al., 2007), and also demonstrated that rescue of the neuronal migration defect is not accompanied by normalisation of brain levels of VLCFA, DHA or plasmalogens (Janssen et al., 2003). Mice deficient in both the L- and D-bifunctional proteins, which are involved in straight- and branched-chain fatty acid oxidation in the peroxisome, show a loss of peroxisomal b-oxidation and elevated brain VLCFA but display no abnormality in neuronal migration (Baes et al., 2002; Verheijden et al., 2013), indicating that perturbed fatty acid metabolism is not directly responsible for the neuronal migration defect. Investigations on PEX5-deficient mice have indicated that DHA deficiency is not a major pathogenetic factor as normalisation of DHA levels in pups did not result in clinical improvement or correction of the neuronal migration defect (Janssen et al., 2000). By contrast, mice with targeted deletion of a key peroxisomal enzyme required for synthesis of plasmalogens, dihydroxyacetone phosphate acyltransferase (DAPAT), exhibit cerebellar foliation defects (Teigler et al., 2009). It has been proposed that plasmalogens modulate the toxic cellular impact of VLCFA in brain (Brites et al., 2009), although this was not substantiated in a subsequent study that showed that deficiency of both peroxisomal b-oxidation and ether lipid synthesis led to only a minor defect in neuronal migration (Krysko et al., 2010). Mice deficient in PEX11b, a peroxisomal membrane protein involved not in protein import but in peroxisome division and proliferation, also exhibit many of the pathological features of the PEX2-, PEX5- and PEX13-deficient Zellweger syndrome mice, including neonatal lethality and minor neuronal migration and developmental delay, but show little to no perturbation of peroxisomal metab-

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olism, structure or abundance (Li et al., 2002). These animals therefore have, albeit restricted, pathological hallmarks of Zellweger syndrome without the cellular hallmarks, which again suggests that disturbances in peroxisomal metabolic pathways per se do not directly cause disease pathogenesis. Thus in terms of the molecular pathogenesis of ZS, the implications of the findings from mouse models has been equivocal in providing a direct link between a specific metabolic deficit and neuropathogenesis. 5. Mitochondrial dysfunction and oxidative stress The redox state of a cell represents a fine balance between the rate of production of reactive oxygen (and nitrogen) species (ROS) and the activity of the protective antioxidant activities – oxidative stress refers to an imbalance that gives rise to increased steady state levels of ROS and resultant damage to cellular macromolecules. Neurons are especially sensitive to oxidative stress, which can induce cell death. Elevated levels of ROS, and the accompanying oxidative (and nitrosative) damage, are a common feature of many neurodegenerative diseases, and are intimately associated with disease progression (Dawson and Dawson, 2003; Andersen, 2004). ROS may also adversely affect neurodevelopment through perturbation of function of a range of biomolecules – lipids, proteins, DNA – and associated signal transduction, with susceptibility occurring during both embryonic and fetal stages in the mouse (reviewed in Wells et al. (2009)). Peroxisomes and mitochondria are the two predominant cellular organelles that contribute to redox control. Mitochondria are the major source of ROS in cells, with superoxide (O2 ) the predominant primary species generated by the electron transport chain during the production of ATP. Superoxide is a by-product of this pathway that arises at two sites in the electron transport chain, viz. complex I (NADH:CoQ oxidoreductase) and complex III (CoQcytochrome c oxidoreductase) (Turrens, 1997). O2 is metabolised by superoxide dismutase (SOD) to the less potent, but longer-living hydrogen peroxide (H2O2). Matrix O2 generated by complex 1 is metabolised by the matrix MnSOD, whereas complex III-generated inter-membrane space O2 is metabolised by the intermembrane space Cu/ZnSOD (SOD1). It has been demonstrated that generation of superoxide anion from the respiratory chain activity is accelerated by complex I deficiency (Pitkanen and Robinson, 1996) and conversely that lipid peroxidation damages complex 1 and also leads to induction of the mitochondrial permeability transition. The peroxisome is also a repository for many important antioxidant enzymes, including the major H2O2-degrading enzyme catalase. H2O2 is central to ROS metabolism in peroxisomes. Peroxisomes contain a variety of oxidase enzymes that generate H2O2 as part of their catalytic action, and together have been estimated to generate more than one-third of the total H2O2 in rat liver in vitro (Boveris et al., 1972). Decomposition of oxidase-generated H2O2 to H2O and O2 is primarily carried out by catalase via an extremely efficient catalatic mechanism (Deisseroth and Dounce, 1970; Chance et al., 1979), thereby maintaining redox balance under normal physiological conditions. The H2O2 produced from the mitochondrial pathways is either metabolized by the resident mitochondrial glutathione peroxidase, or diffuses out of the mitochondrion into the cytoplasm for subsequent uptake and metabolism by peroxisomal catalase (Finkel and Holbrook, 2000; Wallace and Fan, 2009; Martin, 2012). Although of primary importance, catalase is only one component of the antioxidant enzyme repertoire found in peroxisomes of mammalian cells. Other H2O2-metabolizing enzymes include glutathione peroxidase, peroxiredoxin I, Cu, Zn-containing SOD, and epoxide hydrolase (Schrader and Fahimi, 2004).

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Evidence for oxidative stress and oxidative damage in brain of ZS patients is limited, and is mainly indirect or implied (Nordgren and Fransen, 2013). El-Bassyouni et al. (2012) recently demonstrated increased plasma levels of the oxidative stress markers malondialdehyde and nitric acid in ZS patients. A direct involvement of mitochondria and mitochondrial oxidative pathways in ZS pathogenesis has not been widely considered until recently, even though mitochondrial abnormalities were identified in one of the earliest investigations of ZS human patients – Goldfischer et al. (1973) in a landmark paper, reported that mitochondria in hepatocytes and cortical astrocytes were distorted in appearance, and mitochondrial electron transport was defective. Similar findings for liver mitochondria have been reported following a histopathological analysis of a larger patient cohort (Hughes et al., 1990). Mice with peroxisome deficiency exhibit abnormal mitochondrial morphology and function. PEX5-null (Baes et al., 1997; Baumgart et al., 2001) and PEX13-null (Maxwell et al., 2003) mice accumulate dysmorphic mitochondria in liver and brain, with liver complex 1 activity reduced by more than 40% (Baumgart et al., 2001). Cultured cerebellar neurons from E19 PEX13-null mice also exhibit elevated levels of ROS, induction of MnSOD (but not SOD1), and increased neuronal cell death (Muller et al., 2011). These results parallel the reported elevation of MnSOD in liver and heart of PEX5-null animals (Baumgart et al., 2001) and are indicative of increased production of ROS by the mitochondrial electron transport chain at complex 1, and reduced liver complex 1 activity for PEX5-null mice. In a separate study, Faust (2003) demonstrated increased cerebellar neuronal apoptosis for PEX2 mutant mice, a proposed explanation for this being an altered oxidative status in peroxisome-deficient cells. Overall, these findings are compatible with a proposed mechanism of mitochondrial-mediated oxidative stress and neuronal cell death. However other research has not supported a role for oxidative stress. Bottelbergs et al. (2012) for example have reported that the demyelination, macrophage activity, and axonal loss of NestinCre-PEX5 mice were not accompanied by generalised oxidative stress throughout the brain. Thus, although there are some suggestions of links, the exact contributions of mitochondria and oxidative stress to the neuropathogenesis of ZS remain unclear. The other related consideration is the role of ROS in cell signalling, which involve separate pathways to those of ROS-mediated oxidative tissue damage. This is considered further below. 6. Peroxisome–mitochondrion cross-talk Under normal physiological conditions there is significant functional cross-talk and mechanistic overlap between peroxisomes and mitochondria. These organelles are known to exhibit metabolic cross-talk through a number of pathways – with cellular fatty acid b-oxidation, for example, the shortened fatty acids from the peroxisomal b-oxidation system are transported to the mitochondrion for further rounds of b-oxidation chain shortening (Wanders and Waterham, 2006; Wanders, 2013). The overlap between these organelles can be traced even further back to the mechanisms of organelle formation, in that transcriptional control of the biogenesis of these two organelles is coupled. In particular, expression of the peroxisome proliferatoractivated receptor c coactivator 1a (PGC-1a) protein regulates both mitochondrial and peroxisomal biogenesis, including transcriptional control of key enzymes involved in redox control (Austin and St-Pierre, 2012). Furthermore, these organelles share common machinery in their pathways of membrane fission, including the proteins DRP1, Mff, and hFis1 (Koch et al., 2005; Schrader, 2006; Kobayashi et al., 2007). A direct disease link to these fission processes is provided by a heterozygous, dominant-negative mutation in DLP1 in humans that leads to abnormalities in

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both mitochondria and peroxisomes and a neonatal lethal disease with abnormal brain development (Waterham et al., 2007). Interestingly, peroxisome elongation, a precursor to peroxisome fission, is induced by DHA, a product of peroxisome metabolism (Itoyama et al., 2012). This structural and functional overlap of the two organelles has been expanded to include a small-vesicular mediated pathway for cargo transport from mitochondria to peroxisomes (Neuspiel et al., 2008). Given this metabolic and biogenetic cross-talk, the consequences of peroxisome deficiency/dysfunction potentially include altered intermediary metabolism, compromised redox control, and specific deleterious effects on mitochondrial structure and function. In this regard, then, the recent finding of Wang et al. (2013) is of particular interest, in indicating that mitochondria are targets for oxidative stress arising from peroxisomes, and that peroxisomal deficiency sensitizes cells to oxidative stress, indicating the existence of an important redox-dependent signalling pathway between the two organelles. This finding provides a possible clue to the mitochondrial abnormalities that occur in ZS, and by inference at least some of the pathological changes in brain. The proposed role of mitochondria in ZS neuropathogenesis is not limited to the more widely recognised role of mitochondrial dysfunction in neurodegeneration. Recent findings have led to the suggestion that mitochondria – through important processes such as mitochondrial biogenesis, mitophagy, and trafficking – are also crucial for brain development and synaptic pruning (reviewed by Hagberg et al. (2014)).

7. a-Synuclein oligomerisation A characteristic of neurodegenerative disease is the propensity for neurons to accumulate specific misfolded proteins into small toxic oligomers. The modified protein is commonly recognized as a signature protein for that disease, and its accumulation leads to activation of the ubiquitin–proteasome and/or autophagic/lysosomal pathways of protein degradation (Soto and Estrada, 2008; Nakamura and Lipton, 2009). Accumulation of brain VLCFA, as a result of deficiency of peroxisomal fatty acid b-oxidation, is a feature of ZS patients and at least some mouse models of ZS (but see below). The profile of accumulated VLCFA for ZS patients (Sharp et al., 1987) includes very-long-chain (PC26) polyenoic polyunsaturated fatty acids (PUFA), and a similar change occurs in the brains of ZS-like mice (Baes et al., 1997; Faust and Hatten, 1997; Maxwell et al., 2003). Yakunin et al. (2010) examined the possibility that accumulated PUFA trigger a-synuclein oligomerisation in brains from PEX2-, PEX5- and PEX13-null mice. These investigations demonstrated increased levels of a-synuclein oligomerisation and phosphorylation, changes that were correlated with a specific class of fatty acid, viz. x-6 PUFA, findings that suggest a potential link between peroxisomal dysfunction (accumulation of x-6 PUFA) and a-synuclein oligomerisation. The synucleinopathies represent a category of neurodegenerative disease that includes Parkinson’s disease (PD) and related diseases such as dementia with Lewy bodies (DLB) (Jellinger, 2003). As a group, these diseases exhibit increased content and/or aggregation of the a-synuclein protein in brain neurons. The effects of elevated levels of a-synuclein on cellular function are still being unravelled, however some investigations have identified a specific interaction with mitochondria (Nakamura et al., 2008) and a direct effect on mitochondrial complex 1 activity and mitophagy (Chinta et al., 2010), although in a separate study mitochondrial effects were dissociated from the oligomeric state and pathological roles of a-synuclein (Loeb et al., 2009). The proposed role of a-synuclein oligomerisation in ZS neuropathogenesis is confounded by the veracity of the proposition that

VLCFA levels underpin ZS neuropathogenesis, as discussed above. Thus, although elevated levels of a-synuclein oligomers are a characteristic of the ZS mouse brains, the link to VLCFA/PUFA levels as a ZS pathogenetic mechanism is yet to be established, and therefore the consequences of elevated a-synuclein oligomers in the ZS mouse brains remains to be established. Importantly, there is no published information on the presence of a-synuclein oligomers in human ZS brains, so this interesting avenue of investigation awaits further research. 8. Neuroinflammation Neuroinflammation is an immune response of the brain to cellular stress, which can be caused by infectious agents as well as endogenously produced chemicals. The innate immune component of such a response involves primarily microglia, but also astrocytes and oligodendrocytes, and results in clearance of apoptotic cells. An adaptive immune response may also be involved through recruitment of activated T- and B-cells (Taylor et al., 2013). Inflammation has not been reported as a common feature of ZS brains, although astrocytes and radial glia have been reported to contain abnormal pleomorphic cytosomes (Powers et al., 1989). In contrast, neuroinflammation is an established feature of mouse models of ZS and related peroxisomal diseases. For example, mice with peroxisome-deficient oligodendrocytes display neuroinflammation that correlates with axonal loss (Kassmann et al., 2007). Also, mice with conditional brain inactivation of PEX5 and PEX13 show both astrogliosis and activated microglia (Hulshagen et al., 2008; Muller et al., 2011; Bottelbergs et al., 2012). Activation of the innate immune system was determined to be a very early event in the neuropathological process of NesCre-PEX5 mice, and prior to identifiable pathologies such as axonal loss (Bottelbergs et al., 2012). In addition, targeted peroxisome deficiency in oligodendrocytes leads to axonal loss, subcortical demyelination and causes pronounced neuroinflammation, indicating an important neuroprotective role played by peroxisomes in oligodendrocytes (Kassmann et al., 2007). Of the different brain cells, oligodendrocytes also have the greatest capacity for ROS detoxification (Hirrlinger et al., 2002). Interestingly, in an unrelated but complementary approach, Gray and co-workers tested the hypothesis that peroxisomes protect neurons from inflammatory damage (Gray et al., 2011, 2012). They demonstrated that agonists of peroxisome proliferator-activated receptors, which increased peroxisome numbers and function, protected cortical neurons against both nitric oxide donor-induced and microglia-derived nitric oxide-induced toxicity. The peroxisomal b-oxidation pathway also provides a link with inflammation, in that degradation of eicosanoids, substrates of the b-oxidation pathway, is important in maintaining appropriate physiological concentrations of arachidonic acid, eicosapentaenoic acid and their derivatives – prostaglandins, leukotrienes, prostacyclins and thromboxanes – which are known mediators of inflammatory pathways (Chapkin et al., 2009; Trompier et al., 2013). Thus, loss of peroxisomal b-oxidation potentially impacts a range of inflammatory processes in brain. 9. Peroxisomes and cell signalling There is emerging evidence that peroxisomes play important roles in cell signalling – the inflammatory mediators noted above provide important examples. Early findings on research on the PEX5-null mouse suggested that the neuronal migration disorder in Zellweger mice is

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secondary to glutamate receptor dysfunction, and that this could be partially restored in PEX5-deficient neuronal cells in culture by addition of platelet activating factor (PAF) (Gressens et al., 2000). Again, through its role in redox control, the peroxisome contributes to regulation of ROS levels in the cell, with ROS and reactive nitrogen species (RNS) acting to promote critical pathways of cell proliferation and cell survival (Nordgren and Fransen, 2013). Hydrogen peroxide is a ROS with an established role in cell signalling (Gough and Cotter, 2011). So perturbation of redox control through the loss of peroxisomal redox pathways would be expected to pose significant challenges for the cell, one of which is proposed to be the activation of pathways of mitochondrial-mediated cell death (Titorenko and Terlecky, 2011). This also raises the issue of the ‘‘balance’’ between the contribution of hydrogen peroxide to physiological cell signalling and its other potential contribution to oxidative damage. Again, because of their high demand for oxygen, neurons would be especially susceptible to changes in hydrogen peroxide and other ROS/RNS levels. Finally, recent findings have identified a central role for the peroxisome as a signalling platform for innate immunity to viral infection (Dixit et al., 2010) and for tuberous sclerosis complex (TSC) regulation of mTORC1 and autophagy (Zhang et al., 2013). In addition, PEX13, a peroxisomal membrane protein required for matrix protein import in mammals (Liu et al., 1999; Maxwell et al., 2003) has been identified as a candidate mitophagy factor (Orvedahl et al., 2011). The impact of the loss of peroxisomes on such important pathways is likely to be of great general interest in the immediate future, and should better inform our understanding of ZS neuropathogenesis.

10. Concluding comments and perspectives The above considerations have identified a number of factors that may contribute to ZS pathogenesis. The case for any of these factors as the primary trigger of the neuropathogenesis is not compelling. However, it is obvious that many of these individual factors overlap in terms of their metabolic and functional inter-relationships. It is also clear that some of these factors, separately or in combination, have been implicated in other neurodevelopmental disorders (Costa-Mattioli and Monteggia, 2013; Lee et al., 2013; Hagberg et al., 2014) and neurodegenerative diseases (Dawson and Dawson, 2003; Martin, 2012). A number of these factors are further considered below, and some final perspectives included. In terms of a strong pathogenetic factor, mounting evidence implicates mitochondrial dysfunction as a potential trigger of both neurodevelopmental defects (Hagberg et al., 2014) and neurodegeneration (Martin, 2012), and there are several reasons supporting this. For example, in general terms, neurons are highly dependent on oxidative energy metabolism, and correspondingly, abnormal mitochondrial dynamics, morphology, axonal trafficking and function are common features of neurodegenerative disorders (Ischiropoulos and Beckman, 2003; Knott and Bossy-Wetzel, 2008). Similarly, as mitochondria are important in brain development, these same mitochondrial abnormalities have been implicated in neurodevelopmental disorders (Hagberg et al., 2014). The role of mitochondrial dynamics is exemplified by neurodegenerative disease caused by loss-of-function mutations in genes that encode mitochondrial fusion GTPases (Santel, 2006) and through defects in mitochondrial trafficking (Rintoul and Reynolds, 2010). The potential importance of other mitochondrial parameters derives from

A

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1

P

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Peroxisomal dysfunction 4

O2 S oligomers 3

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Fig. 1. Potential steps leading to neurodevelopmental defects and neurodegeneration in ZS. M, mitochondrion; P, peroxisome. 1. A PEX gene mutation leads to loss of peroxisomal protein import, abnormal peroxisome morphology and peroxisomal metabolic dysfunction. Similar changes (not shown) occur in glial cells, such as astrocytes and microglia. 2. Loss of peroxisomes leads to widespread molecular and metabolic changes, including perturbation of cell signalling pathways and redox imbalance. 3. Oxidative stress, PUFA accumulation, or other peroxisome-induced metabolic disturbances induce oligomerization of a-synuclein. 4. Multiple insults on mitochondria, including sensitization of mitochondria to oxidative stress, lead to increased generation of ROS, initiated by enhanced superoxide radical (O2 ) production by the electron transport chain. 5. Reduced mitochondrial function, ROS production, and altered cell signalling lead to reduced neuronal function, synaptic transmission, and neuronal migration, resulting in delayed brain morphogenesis. 6. Similarly, reduced mitochondrial function, ROS-mediated signalling and other unspecified metabolic insults lead to activation of mitochondrial-mediated cell death. 7. Altered neuronal function and/or neuronal cell death may also be triggered, or propagated, by activation of astrocytes (A) and microglia (M), with associated inflammatory response and oxidative stress.

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evidence demonstrating, for example, that most known neuronal death pathways involve mitochondrial complex 1 inactivation (Dawson and Dawson, 2003) and that mitochondrial-mediated apoptosis is responsive to bioenergetic failure and other cellular stressors (Kroemer and Reed, 2000). Based on these considerations, and the emerging evidence to indicate mitochondrial changes in ZS patients and animal models of ZS, a case is building for a mitochondrial contribution to ZS neuropathogenesis. In the context of ZS neuropathogenesis, mitochondria also provide the link to the possible effects of oxidative stress. As noted above, the sensitivity of neurons to elevated levels of reactive oxygen species (ROS) and any accompanying oxidative damage is well established, and may, at least in part, be explained by the relative paucity of antioxidant defense systems in neurons (Lin and Beal, 2006). The mechanism(s) by which such changes trigger neurodegeneration are still unclear, but again a strong link is now emerging between these phenomena and mitochondrial dysfunction (Martin, 2012). In addition, oxidative stress has been implicated in neurodevelopmental disorders through damage to cellular macromolecules and perturbation of cell signalling pathways (Wells et al., 2009). Cell signalling is also emerging as an important factor in ZS neuropathology. The role of the peroxisome in TSC-dependent mTORC1 signalling deserves special note. Dysregulation of mTOR signalling is associated with neurodevelopmental disorders, and in neurons mTORC1 integrates synaptic signals (such as NMDAtype glutamate receptors) through phosphatidylinositol 3-kinase and the TSC. As well as autophagy, mTOR regulates other growth related pathways such as protein synthesis, transcription and lipid synthesis (reviewed by Costa-Mattioli and Monteggia (2013)). As a specific example, there is strong evidence emerging that disruption of normal mTOR-dependent cell autophagy pathways during neurodevelopment causes developmental abnormalities (reviewed by Lee et al. (2013)). The impact of loss of the peroxisome in this context is still unknown, but potentially represents a novel clue to ZS neuropathology. The accumulation of a-synuclein oligomers in brains of peroxisome deficient mice (Yakunin et al., 2010) suggests that these misfolded proteins either contribute to the neuropathology or arise as a consequence of cellular dysfunction – interestingly, there are potential mechanistic explanations supporting both processes. aSynuclein oligomers have been almost exclusively associated with neurodegeneration. In particular, the potential involvement of asynuclein oligomers in Parkinson’s disease neurodegeneration is well recognised, even though the actual mechanisms involved are still controversial (Kalia et al., 2013). Of further interest, however, is that a-synuclein oligomerization has been suggested to enhance mitochondrial oxidative stress (Parihar et al., 2009) as well as occurring as a consequence of oxidative stress (Schildknecht et al., 2013). Indeed, a-synuclein has recently been proposed as the link between oxidative stress, mitochondria, and proteostasis (Schildknecht et al., 2013). Unfortunately, these considerations further confuse the issue, as they do not provide a simple explanation for the presence of a-synuclein oligomers in ZS mouse brain. It is of further interest that a-synuclein oligomers were identified in neonatal (P0.5) mice (Yakunin et al., 2010), indicating that the processes of formation of these oligomers occurs before birth – this suggests a potential impact on neurodevelopmental pathways. Thus, the pathogenetic potential of a-synuclein oligomers warrants further investigation. Neuroinflammation is not a reported feature of ZS brain, but is prominent for ZS mouse brains. This raises two possibilities, either that investigations of ZS patient pathology have not focused on inflammatory changes, and/or that the neuroinflammation seen for the mouse mutants is not modelling the pathology of human patients. At this stage, these possibilities are unable to be satisfactorily answered, and must await more studies. However, neuroin-

flammation and oxidative stress in neurodegeneration are closely linked phenomena (Taylor et al., 2013). To add to the complexity, it has been proposed that a-synuclein is an established trigger of the innate immune response in neurodegenerative disease (Austin et al., 2006; Rojanathammanee et al., 2011). This review, for simplicity, has focused on ZS as the prototypical peroxisome biogenesis disorder with severe neuropathology. It should be noted, however, that another peroxisomal disorder, Dbifunctional protein (D-BP) deficiency, which results specifically from the deficiency of this peroxisomal enzyme – and therefore not due to defective peroxisome biogenesis – also presents clinically with severe neurological deficits that make it difficult to distinguish from ZS (Moller et al., 2001; Huyghe et al., 2006). Indeed, in recognition of the similar clinical and cellular features of these two disorders, we have previously proposed a common pathogenetic mechanism that involves abnormal peroxisome trafficking along microtubules (Nguyen et al., 2006). In the context of this review, the similar neurological features of ZS and D-BP deficiency provide another piece of evidence that supports the hypothesis that the pathogenetic mechanisms are not simply due to an isolated metabolic deficiency, but instead to wider cellular responses to abnormal peroxisome structure and/or function. In conclusion, many of the proposed major contributors to ZS pathogenesis, and their possible inter-relationships, are depicted in Fig. 1. The challenge that remains is to understand the links between many of these identified cellular changes and the broad range of pathologies that are seen in ZS and the animal models of this disease.

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