Antiapoptotic gene therapy in Parkinsons disease

Department of Neurodegeneration & Restorative Research, Center of Neurology and DFG Research Center "Molecular Physiology of the Brain'' (CMPB), University of Göttingen, Göttingen, Germany

Summary. Apoptosis, whether caspase-dependent or caspase-independent, has been implicated as one of the important mechanisms leading to the death of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Major advances of our understanding of apoptosis have been achieved in studies of 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) toxicity in mice and monkeys and 6-hydroxydopamine (6-OHDA) toxicity in rats and monkeys. The use of viral vectors to either express anti-apoptotic proteins or to downregulate pro-apoptotic proteins has the major advantage of addressing selective molecular targets, bypassing the blood-brain-barrier to specifically target the nigrostriatal pathway by their stereotaxic application and by the choice of the appropriate virus and promotor. Used thus far have been virus-mediated overexpression of inhibitor of apoptosis proteins, inhibitors of the c-jun-N-terminal kinase (JNK) pathway, inhibitors of calpains and dominant negative inhibitors of the protease activating factor (APAF)-1 and cdk5. Most studies implicate the endogenous, mitochondrial pathway in the apoptosis of dopaminergic neurons. The results suggest that only an inhibition of this pathway upstream of caspase activation will also result in the protection of nigrostriatal dopaminergic terminals and behavioral benefit, whereas an inhibition of caspases alone may not be sufficient to prevent the degenera tion of terminals, although it may promote the survival of neuronal cell bodies for some time.

Cell death mechanisms

In recent years, several cell death mechanisms have been implicated in the death of dopaminergic neurons. They include mito-chondrial dysfunction, generation of free radicals, inflammation, apoptosis, excitotoxi-city, necrosis and autophagy. The death of dopaminergic neurons leads to a deficit of dopamine in the striatum, producing symptoms in the patient of rigidity, akinesia and tremor. It has been hypothesized recently that axonal pathology may actually pre-date the degeneration of neurons (Berliocchi et al., 2005) especially in Alzheimer's disease (Cash et al., 2003; Stokin et al., 2005), Huntington's disease (Trushina et al., 2004; Charrin et al., 2005) and amyotrophic lateral sclerosis (Jablonka et al., 2004; Kieran et al., 2005). In addition, Parkinson's disease causing mutations in a-synuclein alter axonal transport (Jensen et al., 1998; Jensen and Gai, 2001; Saha et al., 2004) of a-synuclein. The transgenic overexpression of a-synuclein leads to accumulation in neurites (Kahle et al., 2000; Rathke-Hartlieb et al., 2001) and death of dopaminergic neurons. If loss of axons, terminals and striatal dopamine concentrations pre-date death of dopaminergic neurons then a therapy that prevents the execution of cell death and promotes axonal recovery would not only stop the progression of the disease but also lead to an improvement of the symptoms. Indications for such a possibility of improvement come from transgenic mouse models of Huntington's disease in which in the conditional model of a tetracycline-induced interruption of the extended polyglutamine track of huntingtin leads to a reversal of pathology and symptoms (Yamamoto et al., 2000).

Protein aggregation

Genetic data suggests that failures of the ubiquitin proteasome system could lead to intracytosolic deposition of insoluble protein aggregates consisting of a-synuclein and other proteins (Kriiger et al., 2002; Bossy-Wetzel et al., 2004). It is currently debated, whether the protein aggregates themselves or their precursors, protofibrils, induce neuronal dysfunction and death (Caughey and Lansbury, 2003). Gene therapeutic approaches inducing the expression of heat shock protein (HSP)70 (Dong et al., 2005), or b-synuclein (Hashimoto et al., 2004), which interact with a-synuclein and prevent its aggregation, have protected from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity and a-synuclein aggregation in transgenic animals. Interestingly, conditional expression of parkin in drosophila (Haywood and Staveley, 2004) or virus mediated overexpression of parkin in rats (Yamada et al., 2005) protected against trans-gene-induced a-synucleinopathies.

Because transgenic overexpression of wild-type or mutant a-synuclein leads to a synucleinopathy but - at least in mice - does not reliably induce dopaminergic death, toxin-induced animal models are widely used to study cell death mechanisms in dopami-nergic neurons (Schober, 2004). Furthermore, the exact pathogenic mechanisms are still unknown for the newly identified muta tions in DJ1 (Bonifati et al., 2003), Pinkl (Valente et al., 2004), and LRRK2 (Zimprich et al., 2004), and in the sporadic cases, which still account for the majority of Parkinson's disease patients. In contrast, intoxication of humans, monkeys and mice with MPTP leads to most of the pathological, biochemical and behavioral characteristics of Parkinson's disease including death of dopaminergic sub-stantia nigra neurons, reduction of the concentration of dopamine in the striatum, an inhibition of mitochondrial function, the generation of reactive oxygen species, induction of inflammation, and a reduction of spontaneous locomotion. If indeed the downstream mechanisms and the execution of death in dopaminergic neurons are similar in the genetic and sporadic cases of Parkinson's disease, toxin-induced models of Parkinson's disease will enable the identification of important pathogenetic pathways as well as therapeutic strategies.

Apoptosis

Apoptosis was initially defined by distinct morphological and biochemical alterations. In the classical case, condensation and fragmentation of chromatin, compaction of cyto-plasmic organelles, a decrease in cell volume and alterations of the plasma membrane are observed, resulting in the recognition and phagocytosis of apoptotic cells. Caspases have been identified as the major proteases to execute apoptosis. However, several non-caspase-mediated forms of apoptosis have also been reported. The following cell death forms have been identified and summarized (Leist and Jaattela, 2001):

(i) classical apoptosis;

(ii) apoptosis-like programmed cell death, in which the chromatin condensation characteristically is less compact and complete than in apoptosis (the typical feature found in non-caspase-mediated forms of programmed cell death including autophagy - characterized by the formation of large, lysosome-derived cytosolic vacuoles - and ''dark cell death'');

(iii) necrosis-like programmed cell death, in which chromatin condensation is lacking (the initiation of this cell death may be dependent on caspase activation, however the execution is independent of caspases); and

(iv) accidental necrosis and cell lysis.

Based on morphological grounds, the results to detect apoptosis in dopaminergic substan-tia nigra neurons post mortem in brains from patients that had suffered from Parkinson's disease were controversial. Reported figures of apoptotic dopaminergic neurons range from 5% to 8% on the one hand (Mochizuki et al., 1996; Anglade et al., 1997; Tompkins et al., 1997), whereas others failed to detect apoptotic changes at all (Kosel et al., 1997; Banati et al., 1998; Wullner et al., 1999). Given the slow and chronic nature of the disease course, the chances to detect morphological alterations of apoptosis or to find evidence for apoptotic DNA fragments will be low, if apoptosis in vivo is executed as quickly as apoptosis in vitro. However, the detection of molecular apoptotic markers in human brain tissue (Hartmann et al., 2000, 2001a) and animals (Tatton and Kish, 1997; Eberhardt et al., 2000) strongly supports the hypothesis that apoptotic mechanisms play an important role in the death of dopaminer-gic neurons. Interestingly, the rate of apopto-tic death compared with non-apoptotic death is higher in paradigms that utilize a chronic rather than an acute paradigm of MPTP intoxication (Jackson-Lewis et al., 1995; Tatton and Kish, 1997). A biochemical hallmark of Parkinson's disease is a reduced activity of complex I of the electron transport chain in the substantia nigra (Schulz and Beal, 1994). Among the first targets of activated caspases are mitochondria themselves, leading to disruption of electron transport, loss of mitochondrial transmem-

brane potential, reduction of ATP concentrations, generation of reactive oxygen species and morphological alterations of mitochondria (Ricci et al., 2003). Recently, the 75 kDa subunit of complex I was identified as a caspase substrate accessible to the intermembrane space of the mitochondria (Ricci et al., 2004). Expression of a noncleavable mutant of p75 protected against mitochondrial dysfunction in response to apoptotic stimuli and delayed cell death but left cytochrome c release from mitochondria and DNA fragmentation unaffected.

Caspases as a target for gene therapeutic intervention

In mice that are chronically intoxicated with MPTP, caspase-3 activation is observed in tyrosine hydroxylase (TH)-positive neurons of the substantia nigra pars compacta (SNpc; Eberhardt et al., 2000; Hartmann et al., 2000; Mochizuki et al., 2001). Until recently, no peptide inhibitors of caspases that pass the blood brain barrier were available. Therefore, intracerebroventricular application offered the only option to deliver the peptide inhibitors to the brain. This approach was successfully used in a transgenic mouse model of amyotrophic lateral sclerosis (Li et al., 2000). Recently, Beal and colleagues reported for the first time that the systemic application of a novel peptidyl broad-spectrum caspase inhibitor, Q-VD-OPH, offered protection against MPTP toxicity (Yang et al., 2004). However, systemic treatment with broad spectrum caspase inhibitors has the disadvantage that physiological functions of cas-pases involved in tumor and immunological defense mechanisms may be compromised as well.

We therefore developed gene based therapies to inhibit caspases. The family of inhibitor of apoptosis proteins, of which one is the X-chromosome linked inhibitor of apoptosis protein (XIAP) are endogenous inhibitors of caspase-3 and caspase-7 (Deveraux and Reed, 1999), and likely caspase-9 as well (Robertson et al., 2000). The anti-caspase activity is mediated by baculoviral-inhibitor of apoptosis repeat domains (BIRs; Clem and Miller, 1994). Stereotaxic injection of an adenovirus into the striatum that mediated the expression of XIAP in the striatum and -after retrograde transport - in dopaminergic neurons of the SNpc also protected from MPTP-induced loss of TH-positive neurons in the SNpc (Eberhardt et al., 2000). However, in this paradigm of 5 x 30 mg/kg MPTP injected i.p. over a period of 5 consecutive days, XIAP expression did not prevent the degeneration of nigrostriatal terminals and the loss of dopamine and its metabolites in the striatum (Eberhardt et al., 2000). These results were confirmed in mice overexpres-sing XIAP (Crocker et al., 2003a). In contrast, in the rat 6-hydroxydopamine model, adenovirally mediated overexpression of the neuronal inhibitor of apoptosis protein (NAIP) (Crocker et al., 2001) protected not only from the loss of dopaminergic SNpc neurons but also from the degeneration of terminals in the striatum (Crocker et al., 2001). In the MPTP model we only achieved an improvement of synaptic function when we combined the adenovirus-mediated expression of XIAP with the expression of GDNF (Eberhardt et al., 2000). This combined gene therapeutic approach provided synergistic effects and prevented the degeneration of TH-positive neurons in the SNpc and their terminals in the striatum. Our data also implicate that the terminals degenerate independently of caspase activity. This hypothesis is supported by preliminary data showing that, on the C57BL/6 background, caspase-3-deficient mice (Houde et al., 2004) are protected from MPTP-induced loss of TH-positive neurons in the SNpc but not against the reduction of dopamine concentrations in the striatum (Rathke-Hartlieb and Schulz, unpublished). More generally, Nicotera and colleagues (Berliocchi et al., 2005) demonstrated a temporal and mechan istic dissociation of cell death mechanisms underlying the degeneration of neurites and neuronal bodies. Neurites degenerate at an early stage by an active caspase-independent fragmentation characterized by segregation of energy competent mitochondria. Later, the cell body mitochondria release cyto-chrome c, which is followed by caspase activation, morphological changes and cell demise (Berliocchi et al., 2005).

Therapeutic interference with the initiation of apoptosis

The activation of caspases may occur through the external, death receptor-mediated pathway or the internal, mitochondria-mediated pathway (Fig. 1). In the external pathway, the activation of Fas/CD95 or other members of the tumor necrosis factor (TNF) superfamily leads to a direct activation of caspase-8 via interaction with death domains. Activated caspase-8 may activate executioner caspases directly, e.g. caspase-3, or may cleave Bid, a pro-apoptotic member of the Bcl-2 family, which then promotes cyto-chrome c release (Hengartner, 2000), providing a cross link between the mitochondrial and the death receptor pathway of caspase activation. MPTP application does not only lead to the activation of the effector caspase-3 but also the initiator caspases (caspase-8 and caspase-9) and Bid cleavage, and to mitochondrial cytochrome c release (Hartmann et al., 2001b; Viswanath et al., 2001). These changes were attenuated in transgenic mice neuronally expressing the general caspase inhibitor protein baculoviral p35 (Viswanath et al., 2001). Caspase-9 inhibition prevented the activation of both cas-pase-3 and caspase-8 and also inhibited Bid cleavage, but not cytochrome c release. These data would be compatible with a model of cytochrome c-induced caspase-9 activation leading to caspase-3 activation that mediates the effector phase of apoptosis, and with an amplification loop involving caspase-8.

Mptp Caspase

Fig. 1. Pathways of MPTP/MPP+ -mediated caspase-dependent apoptosis. Apoptosis may be induced by the endogenous, mitochondria-mediated pathway (left side) or by the exogenous, cell death receptor mediated pathway (right side). In healthy neurons, the sensitivity to FasL/CD95L is blocked by the expression of LFG. The JNK pathway appears to play a crucial role for the activation of the mitochondrial pathway. The release of cytochrome c and other factors from mitochondria is probably induced by the transcriptional regulation of pro-apoptotic factors, e.g. the BH3 only, proapoptotic members of the Bcl-2 family which include Bim

Fig. 1. Pathways of MPTP/MPP+ -mediated caspase-dependent apoptosis. Apoptosis may be induced by the endogenous, mitochondria-mediated pathway (left side) or by the exogenous, cell death receptor mediated pathway (right side). In healthy neurons, the sensitivity to FasL/CD95L is blocked by the expression of LFG. The JNK pathway appears to play a crucial role for the activation of the mitochondrial pathway. The release of cytochrome c and other factors from mitochondria is probably induced by the transcriptional regulation of pro-apoptotic factors, e.g. the BH3 only, proapoptotic members of the Bcl-2 family which include Bim

Death receptor, exogenous pathway of apoptosis

In accordance with the results and hypotheses mentioned and in contrast to results obtained in lymphocytes and glial tumor cell lines, exogenous application of FasL/CD95L did not induce death in dopaminergic SH-SY5Y cells (Gomez et al., 2001) or primary mesencephalic cultures (von Coelln and Schulz, unpublished). It was therefore unexpected that Hayley and colleagues found protection from MPTP-induced loss of dopaminergic neurons in Fas/CD95 deficient mice (Hayley et al., 2004). However they did not find protection against the loss of terminals. In addition they observed increased expression of Fas in the substantia nigra after MPTP application. Because c-jun is a transcription factor for Fas/CD95, the authors investigated the effects of an adenovirus mediating the expression of dominant-negative c-jun. Expression of dominant-negative c-jun in the nigrostriatal system protected from the induction of Fas/CD95 and loss of dopaminergic SNpc neurons. Interestingly, Fas-deficient mice displayed a pre-existing reduction in striatal dopamine levels and locomotor behavior when compared with wild-type mice. This finding is in line with a recent demonstration of mice with absent Fas/CD95 (lpr mice) or FasL/CD95L (gld mice) function that exhibited a reduced number of dendritic branches in vivo at the time when synapse formation took place (Zuliani et al., 2006) without affecting the number of neurons. The branching increase occurred in a caspase-indepen-dent and death domain-dependent manner. Furthermore, lentivirus-mediated expression of CD95L/FasL in vitro and in vivo did not induce apoptosis. We recently confirmed that neurons express Fas but are resistant to FasL/CD95L in vitro (Beier et al., 2005). This resistance was mediated by the lifeguard (LFG)/neuronal membrane protein (NMP)35 that co-localizes and physically interacts with Fas/CD95, thereby preventing the induction of the exogenous, Fas/CD95 mediated apo-ptosis pathway (Somia et al., 1999; Beier et al., 2005). Downregulation of LFG expression by antisense oligonucleotides or small interfering RNA led to increased sensitivity of neurons to FasL/CD95L-induced apopto-sis and re-installed the caspase-8 dependent cell death pathway. Because the expression of LFG is transcriptionally regulated by the phosphatidylinositol 3-kinase (PI 3-kinase)-Akt/protein kinase B (PKB) pathway (Beier et al., 2005), neuronal sensitivity to FasL/ CD95L may occur under pathological conditions in which the PI3-kinase and/or Akt activity is inhibited. This may explain the resistance of gld and lpr mice against cerebral ischemia and spinal trauma and why neutralizing antibodies against FasL/CD95L CD95L provide protection in these paradigms (Martin-Villalba et al., 1999, 2001; Demjen et al., 2004).

An inhibition of the PI3-kinase/Akt pathway under pathological conditions may also be the reason for the observed resistance of Fas/CD95-deficient mice to MPTP toxicity. To date, however, this possibility has not been tested. Alternative explanations arise from the specific requirements of the MPTP model. To become toxic, MPTP requires the conversion to its active, toxic metabolite,

MPP+ through non-neuronal monoamine oxidase B activity, and subsequently the uptake of MPP+ into dopaminergic neurons by the dopamine transporter. Although Hayley and colleagues (Hayley et al., 2004) ruled out that in Fas/CD95 deficient mice the striatal concentration of MPP+ was lower than in wild-type controls, they did not study the density of dopamine uptake sites. Because they themselves reported a reduced density of nigrostriatal fibers, a reduction in the density of the dopamine transporter appears to be a likely explanation for the resistance against MPTP in Fas/CD95-defi-cient mice.

Mitochondrial, endogenous pathway of apoptosis

Together with procaspase-9 the apoptotic protease activating factor (APAF)-1 forms the apoptosome that is activated and leads to the release of active caspase-9 after binding of cytochrome c, which is translocated from mitochondria to the cytosol after an apoptotic stimulus. Using an adeno-associated virus, Mochizuki and colleagues (Mochizuki et al., 2001) delivered an APAF-1 dominant negative inhibitor to the striatum of C57Bl/6 mice and demonstrated protection against the loss of dopaminergic SNpc neurons induced by subsequent MPTP toxicity. In contrast, virus mediated expression of a dominant negative inhibitor of caspase-1 was not protective. These results emphasize the importance of the endogenous, mitochon-drial death pathway in MPTP toxicity. In addition, transgenic mice overexpressing Bcl-2 are protected from MPTP toxicity (Offen et al., 1998; Yang et al., 1998) as well as mice with deficient for Bax (Vila et al., 2001).

Persistent activation of the c-jun-N-term-inal kinase (JNK) pathway has been demonstrated in various apoptotic cell death paradigms (Davis, 2000) and is considered to be one of the major pathways to initiate the release of pro-apoptotic factors from the mitochondria. The exact mechanisms how JNK initiates this pathway are still hypothetical and may be diverse depending on the paradigm. This may involve the trans-criptional induction of pro-apoptotic Bcl-2 family members, e.g. Bid or Bim. JNK-dependent expression of Bim and its importance for the induction of neuronal apoptosis has been shown in primary cerebellar granule neurons (Harris et al., 2002).

The phosphorylation and thereby activation of JNK is a multi-step process that involves the activation of several upstream kinases of the mixed lineage kinase (MLK) family and the formation of protein complexes to ensure signaling specificity. Scaffold proteins have been identified that facilitate the formation of these complexes required for the activation of JNK. One important member is the JNK interacting protein (JIP)-1. We reasoned that the forced expression of the JNK binding domain of JIP-1 would prevent the phosphorylation of JNK. Adenovirus-mediated forced expression of JIP-1 in the nigrostriatal pathway blocked the MPP+/MPTP-induced activation of JNK and c-jun, the activation of caspase-9 and caspase-3 in SH-SY5Y cells in vitro as well as in the SNpc in vivo (Xia et al., 2001). Dopaminergic neurons and their striatal terminals were protected from MPTP-induced death and the mice showed behavioral improvement in amphetamine-induced rotational behavior. These data suggest that interference with the apoptotic cascade upstream of mitochondria may result in better functional protection than just inhibiting the executioner part of apoptosis, e.g. by caspase inhibition. Because MPTP leads to the induction of Bim expression, this JNK-mediated pathway is likely to be functional in MPTP toxicity but may not be the only one. In addition, JNK has been shown to upregulate the expression of COX2 (Hunot et al., 2004), whose neuronal expression is instrumental for MPTP toxicity (Teismann et al., 2003). The functional significance of the JNK pathway for MPTP toxicity is further supported by the effects of the mixed lineage kinase (MLK)-3 inhibitor, CEP-1347 (Saporito et al., 1999, 2000).

Other anti-apoptotic gene therapeutic strategies

In an attempt to inhibit non-caspase mediated apoptosis, Park and colleagues induced forced expression of calpastatin (an inhibitor of calpains) and dominant-negative cdk5 by adenoviral infection of the nigrostriatal pathway. Both strategies provided protection against MPTP toxicity and point to an additional, alternative cell death pathway (Crocker et al., 2003a, b). Further, infection with adeno-associated viruses to express HSP70 resulted in protection from MPTP-induced apoptosis, suggesting that this therapy with chaperons may have direct anti-apoptotic properties as well as affecting the pathological aggregation of proteins (Dong et al., 2005).

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Author's address: Prof. Dr. J. B. Schulz, Department of Neurodegeneration & Restorative Research, CMPB and Center of Neurology, University of Göttingen, Waldweg 33, 37073 Gottingen, Germany, e-mail: [email protected]

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