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is a progressive and severely disabling neurological disease in humans characterized by initial muscle weakness, and then muscle atrophy, spasticity, and eventual paralysis and death typically 3 to 5 years after symptoms begin [403]. The cause of the spasticity, paralysis and death is progressive degeneration and elimination of upper motor neurons in cerebral cortex and lower motor neurons in brainstem and spinal cord (Figure 5) [403,404]. Degeneration and loss of spinal and neocortical interneurons has also been found in human ALS [405,406]. More than 5000 people in the USA are diagnosed with ALS each year (ALS Association, http://www.alsa.org), and, in parts of the United Kingdom, three people die every day from some form of motor neuron disease (http://www.mndassociation.org). Other than life support management, no effective treatments exist for ALS [225].\nIt is still not understood why specific neuronal populations are selectively vulnerable in ALS, such as certain somatic motor neurons and interneurons [404,405,406]. The molecular pathogenesis of ALS is understood poorly, contributing to the lack of appropriate target identification and effective mechanism-based therapies to treat even the symptoms of this disease. Two forms of ALS exist: idiopathic (sporadic) and heritable (familial). The majority of ALS cases are sporadic with few known genetic contributions, except for missense mutations in TAR-DNA binding protein [407]. Aging is a strong risk factor for ALS because the average age of onset is 55 (ALS Association, www.alsa.org). Familial forms of ALS have autosomal dominant or autosomal recessive inheritance patterns and make up ~10% or less of all ALS cases. ALS-linked mutations occur in the genes (Table 4) encoding SOD1 (ALS1), Alsin (ALS2), senataxin (ALS4), fused in sarcoma (FUS, ALS6), vesicle associated membrane protein (VAMP/synaptobrevin)-associated protein B (VAPB, ALS8), p150 dynactin (DCTN1), and TAR-DNA binding protein (TADBP or TDP43) [5,408]. Most recently, variations in the phosphoinositide phosphatase FIG4 gene cause ALS11 [409]. Several other genes are believed to be susceptibility factors for ALS (Table 4).\nFigure 5 Motor neurons in spinal cord degenerate in people with ALS. A, B. In normal individuals, the spinal cord contains many large, multipolar motor neurons (dark cells). C, D. In ALS, the anterior horn is depleted of large neurons (dark cells) and remaining neurons are atrophic. E-G. Nissl staining shows motor neurons that appear normal (E), attritional (F), and residual (G). H. ALS motor neurons accumulate DNA double-strand breaks in the nucleus (brown labeling). I. p53 (brown labeling) accumulates in the nucleus of motor neurons. J. ALS motor neurons are immunopositive for cleaved caspase-3 (black-dark green labeling), and discrete mitochondria (brown-orange labeling, detected with antibody to cytochrome c oxidase subunit I) accumulate around the nucleus (pale circle). Scale bars: A, 500 μm (same for C); B, 76 μm (same for D); E, 6 μm (same for F,G); H, 12 μm (same for I,J).\nTable 4 Mutant/Polymorphic Genes Linked to Familial ALS.\nLocus Inheritance Gene Protein Name/ Function\nALS1/21q22 autosomal dominant (adult onset) SOD1 Cu/Zn superoxide dismutase/ dismutation of superoxide\nALS2/2q33.2 autosomal recessive (juvenile onset primary lateral sclerosis) Alsin Alsin/guanine exchange factor for RAB5A and Rac1\nALS4/9q34 autosomal dominant (adult onset) SETX Senataxin/helicase, RNA processing\nALS6/16q12 autosomal recessive (adult onset) FUS Fused in sarcoma, component of heterogeneous nuclear ribonuclear protein complex; RNA/DNA binding protein\nALS8/20q13.33 autosomal dominant VAPB VAMP-associated protein B/part of SNARE complex\n2q13 autosomal dominant (adult onset, atypical ALS) DCTN1 Dynactin p150glued/axonal transport, link between dynein and microtubule network\nALS10/1p36.22 autosomal dominant TARDBP TAR DNA binding protein, DNA and RNA binding protein, regulates RNA splicing\nALS11/6q21 autosomal recessive FIG4 FIG4 homolog, SAC1 lipid phosphatase domain containing protein; regulates phosphotidylinositol turnover\n14q11.1-q11.2 susceptibility factor ANG Angiogenin; angiogenesis; stimulates production of rRNA\n22q12.2 susceptibility factor NEFH Neurofilament, heavy polypeptide; neurofilament subunit\n12q12-q13 susceptibility factor PRPH Peripherin; intermediate filament formation\n5q13 susceptibility factor SMN Survival motor neuron; RNA processing\n7q36.6 susceptibility factor? DPP6 Dipeptidyl-peptidase 6; S9B serine protease, binds voltage-gated potassium channels\n\nMitochondrial Dysfunction in Human ALS\nMitochondrial abnormalities have been found in human ALS. Structural abnormalities in mitochondria are seen by electron microscopy in skeletal muscle, liver, spinal motor neurons and motor cortex of ALS patients [410,411]. A mutation in cytochrome c oxidase subunit I was found in a patient with a motor neurons disease phenotype [412]. Another patient with motor neuron disease had a mutation in a mitochondrial tRNA gene [413]. One type of mitochondrial DNA (mtDNA) mutation, called the common mtDNA deletion (mtDNA4977), is found non-uniformly within different human brain areas; the highest levels are detected in the striatum and SN [414,415]. However, no significant accumulation of the 5 kb common deletion in mtDNA has been found by single-cell analysis of motor neurons from sporadic ALS cases [416]. Some ALS patients with defects in skeletal muscle mitochondrial oxidative phosphorylation have a novel SOD1 gene mutation [417]. More work on human ALS and animal/cell models needs to be done to determine conclusively if mitochondrial abnormalities participate in disease-causing mechanisms of human ALS.\nIntracellular Ca2+ abnormalities and excitotoxicity are suspected links to mitochondrial dysfunction and oxidative stress in ALS. Mitochondria function in the regulation of intracellular Ca2+ levels [7,418]. Skeletal muscle biopsies of patients with sporadic ALS show ultrastructural changes indicative of elevated Ca2+ in motor neuron terminals, with some mitochondria showing an augmented Ca2+ signal [419]. Utilizing specific transport systems, mitochondria can pump Ca2+ from the cytosol into the matrix by the Ca2+ uniporter and eject Ca2+ from the matrix via the Na+/Ca2+ exchanger [7] and more catastrophically through the mPTP [50]. Under conditions of elevated cytoplasmic Ca2+, whenever the local free Ca2+ concentration rises above a set-point of ~0.5 μM, mitochondria avidly accumulate Ca2+ to a fixed capacity [7]. The electrical gradient across the IMM, the ΔΨm, established by electron transport chain activity (Figure 2), provides the driving force for the accumulation of Ca2+ into the mitochondrial matrix [418]. Cytosolic Ca2+ concentrations above set-point levels are believed to be achieved during tetanic stimulation and by activation of glutamate receptors on the plasma membrane [7]. In pathological settings of excitotoxicity, resulting from excessive overstimulation of glutamate receptors [190,191], Ca2+ overload in neurons is significant and causes cell death [420]. When mitochondria become overloaded with Ca2+, they undergo mPT resulting in osmotic swelling and rupture of the OMM (Figure 1). Mitochondria within synapses appear to be more susceptible than non-synaptic mitochondria to Ca2+ overload [421].\nExcitotoxicity has been implicated in the pathogenesis of ALS for a long time [422] and is another possible mechanism of motor neuron damage in ALS [420]. While many drugs targeting excitotoxicity as a mechanism have failed in ALS clinical trials, the anti-excitotoxic drug riluzole is currently approved by the Food and Drug Administration for ALS treatment. Many sporadic ALS patients have reduced levels of synaptosomal high-affinity glutamate uptake [422] and astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2 or GLT1) in motor cortex and spinal cord [423]. Reductions in levels of activity of EAAT2 in spinal cord could increase the extracellular concentrations of glutamate at synapses on motor neurons. Motor neurons might be particularly sensitive to glutamate excitotoxicity because they have a low proportion of GluR2-edited or under-edited AMPA subtype glutamate receptor on their surfaces, predisposing these cells to risk of excess Ca2+ entry and mitochondrial perturbations (Figure 1) [424,425]. Cell culture studies show that excess glutamate receptor activation in neurons can cause increased intracellular Ca2+, mitochondrial ROS production, bioenergetic failure, and mitochondrial trafficking abnormalities [426]. Ca2+-induced generation of ROS in brain mitochondria is mediated by mPT (Figure 1) [427]. Motor neurons are particularly affected by inhibition of mitochondrial metabolism which can cause elevated cytosolic Ca2+ levels and increased excitability [428].\nMarkers of oxidative stress and ROS damage are elevated in ALS tissues [429]. In human sporadic and familial ALS, protein carbonyls are elevated in motor cortex [430]. Tyrosine nitration (Figure 1) is elevated in human ALS nervous tissues [431,432,433]. Studies of respiratory chain enzyme activities are discrepant. Studies have shown increases in complex I, II, and III activities in vulnerable and non-vulnerable brain regions in patients with familial ALS-mutant SOD1 [434], but other studies show decreased complex IV activity in spinal cord ventral horn [435] and skeletal muscle [436] of sporadic ALS cases. In sporadic ALS skeletal muscle, reductions in activity of respiratory chain complexes with subunits encoded by the mitochondrial genome are associated with decreased neuronal NOS levels [437]. Alterations in skeletal muscle mitochondria are progressive [438] and could be intrinsic to skeletal muscle and not due merely to neurogenic atrophy, as assumed commonly.\n\nHuman ALS and Mitochondrial-Orchestrated PCD Involving p53\nPCD appears to contribute to the selective degeneration of motor neurons in human sporadic and familial ALS, albeit seemingly as a non-classical form differing from apoptosis (Figure 2 and Figure 5) [224]. Motor neurons appear to pass through sequential stages of chromatolysis (suggestive of initial axonal injury [396]), somatodendritic attrition without extensive cytoplasmic vacuolation, and then nuclear DNA fragmentation, nuclear condensation, and cell death (Figure 5) [224]. Motor neurons in people that have died from sporadic ALS and familial ALS show the same patterns of degeneration [224]. This cell death in human motor neurons is defined by genomic DNA fragmentation (determined by DNA agarose gel electrophoresis and in situ DNA nick-end labeling) and cell loss and is associated with accumulation of mitochondria, cytochrome c, and cleaved caspase-3 (Figure 5) [380,439]. p53 levels increase in vulnerable CNS regions in people with ALS, and p53 accumulates specifically in the nucleus of lower and upper motor neurons (Figure 5) [440]. This p53 is active functionally because it is phosphorylated at serine392 and has increased DNA binding activity [24,440]. However, the morphology of this cell death is distinct from classical apoptosis, despite the nuclear condensation [17,24,224]. Nevertheless, Bax and Bak1 protein levels are increased in mitochondria-enriched fractions of selectively vulnerable motor regions (spinal cord anterior horn and motor cortex gray matter), but not in regions unaffected by the disease (somatosensory cortex gray matter) [224]. In marked contrast, Bcl-2 protein is depleted severely in mitochondria-enriched fractions of affected regions and is sequestered in the cytosol (Figure 1) [224]. Although these western blot results lacked direct specificity for motor neuron events [224], subsequent immunohistochemistry for cleaved capsase-3 has shown numerous positive motor neurons in human ALS spinal cord (Figure 5) [439], but another study reported negative findings [441]. More recently, laser capture microdissection of motor neurons combined with mass spectroscopy-protein profiling have confirmed the presence of intact active caspase-3 in human ALS motor neurons [380].\nThese studies [24,224,380,439,441] support the concept of an aberrant re-emergence of an atypical PCD mechanism, involving p53 activation and redistributions of mitochondrial cell death proteins, participating in the pathogenesis of motor neuron degeneration in human ALS. The morphological and biochemical changes seen in human ALS are modeled robustly and faithfully at structural and molecular levels in axotomy models of motor neuron degeneration in adult mouse [442] but not in the commonly used human mutant SOD1 tg mouse models [381,439]. A role for mitochondria in human ALS pathogenesis is further supported by recent work suggesting that lithium treatment may be beneficial in ALS through mitochondrial autophagy [443].\n\nMitochondrial Pathobiology in Cell and Mouse Models of ALS\nA common genetic mutation in human SOD1 that is linked to familial ALS (Table 4) is the substitution of glycine by alanine at position 93 (G93A) [444]. SOD1 is a metalloenzyme of 153 amino acids (~16 kDa) that binds one copper ion and one zinc ion per subunit (Figure 1) [9]. This enzyme, functioning as a ~32 kDa non-covalently linked homodimer, is responsible for the detoxification and maintenance of intracellular O2•- concentration in the low femtomolar range by catalyzing its dismutation [9,445]. SOD1 is ubiquitous (intracellular SOD concentrations are typically ~10–40 micromolar) in most tissues and possibly greater in neurons [446].\nData from cell culture studies reveal mitochondrial dysfunction, possibly motor neuron selective, in the presence of human mutant SOD1 (mSOD1) [447]. Expression of several mSOD1 variants increases mitochondrial O2•- levels (Figure 1) and causes toxicity in cultured primary embryonic motor neurons [448], neuroblastoma cells [449], and NSC-34 cells (a hybrid cell line with some motor neuron-like characteristics, produced by fusion of motor neuron-enriched embryonic mouse spinal cord cells with mouse neuroblastoma cells) [450]. These responses can be attenuated by over-expression of MnSOD [449]. ALS-mSOD1 variants, compared to human wild-type SOD1, associate more with mitochondria in NSC-34 cells and appear to form cross-linked oligomers that shift the mitochondrial glutathione/oxidized glutathione ratio toward oxidation [447].\nGurney and colleagues were the first to develop tg mice that express human mSOD1 [451,452]. Now, these mice are used widely as an animal model of ALS [439,444]. Human mSOD1 is expressed ubiquitously in these mice by its endogenous promoter in a tissue/cell non-selective pattern against a background of normal mouse SOD1 [451]. Effects of this human mutant gene in mice are profound. Hemizygous tg mice expressing high copy number of the G93A variant of human SOD1 become completely paralyzed and die at ~16–18 weeks of age [451]. G93A-mSOD1 mice with reduced transgene copy number have a much slower disease progression and die at ~8–9 months of age [19,451].\nSpinal motor neurons and interneurons in mice expressing G93Ahigh-mSOD1 undergo prominent degeneration; about 80% of lumbar motor neurons are eliminated by end-stage disease [381,453]. Subsets of spinal interneurons degenerate before motor neurons in G93Ahigh-mSOD1 [381] and some are the glycinergic Renshaw cells [453]. Unlike the degeneration of motor neurons in human ALS (Figure 5) [224], motor neurons in these mice do not degenerate with a morphology resembling any form of apoptosis [215,381,439,454]. The motor neurons degeneration seen in G93Ahigh-mSOD1 mice more closely resembles a prolonged necrotic-like cell death process [381] involving early-occurring mitochondrial damage, cellular swelling, and dissolution [215,381,439,453,454]. Biochemically, the death of motor neurons in G93Ahigh-mSOD1 is characterized by somal and mitochondrial swelling and formation of DNA single-strand breaks prior to DNA double-strand breaks occurring in nuclear DNA and mtDNA [381]. The motor neuron death in G93Ahigh-mSOD1 mice is independent of activation of caspases-1 and -3, and also appears to be independent of capsase-8 and AIF activation within motor neurons [381]. Indeed, caspase-dependent and p53-mediated apoptosis mechanisms might be blocked actively in G93Ahigh-mSOD1 mouse motor neurons, possibly by upregulation of IAPs and blockade in the nuclear import of p53 [381]. More work is needed on the cell death in G93Alow-mSOD1 mice, because these mice could be more relevant physiologically and clinically to the human disease compared to G93Ahigh-mSOD1 mouse.\nMitochondrial pathology has been implicated in the mechanisms of mouse ALS [5], but until recently, most evidence is circumstantial. In different mSOD1 mouse models of ALS, mitochondria in spinal cord neurons exhibit structural pathology [81,381,439,453,454,455,456] and some of the mitochondrial degeneration occurs very early in the course of the disease [381,454]. Mitochondrial ultrastructural microvacuolar damage in motor neurons emerges by 4 weeks of age in G93Ahigh mice [381]. It has been argued that mitochondrial damage in G93Ahigh-mSOD1 mice is related to supra-normal levels of SOD1 and might not be related causally to the disease process because tg mice expressing high levels of human wild-type SOD1 show some mitochondrial pathology [457], but mitochondrial abnormalities have been found histologically also in G93Alow-mSOD1 mice [458]. Thus, mitochondria could be primary sites of human SOD1 toxicity in tg mice irrespective of transgene copy number and expression level of human SOD1, but direct, unequivocal causal relationships have been lacking.\nHuman mSOD1 proteins appear to acquire a toxic property or function, rather than having diminished O2•- scavenging activity [459,460,461], and wild-type SOD1 can gain toxic properties through loss of Zn [448] and oxidative modification [462,463]. A gain in aberrant oxidative chemistry could contribute to the mechanisms of mitochondriopathy in G93Ahigh mice (Figure 1) [12,464]. G93A-mSOD1 has enhanced free radical-generating capacity compared to wild-type enzyme [461] and can catalyze protein oxidation by hydroxyl-like intermediates and carbonate radical (Figure 1) [465]. G93Ahigh mice have increased protein carbonyl formation in total spinal cord tissue extracts at pre-symptomatic disease [466]. Protein carbonyl formation in mitochondrial membrane-enriched fractions of spinal cord is a robust signature of incipient disease [81]. A mass spectroscopy study of G93Ahigh mice identified proteins in total spinal cord tissue extracts with greater than baseline carbonyl modification, including SOD1, translationally controlled tumor protein, and UCH-L1 [467]. Nitrated and aggregated cytochrome c oxidase subunit-I and α-Syn accumulate in G93Ahigh mouse spinal cord [381]. Nitrated MnSOD accumulates also in G93Ahigh mouse spinal cord [381]. Toxic properties of mSOD1 could also be mediated through protein binding or aggregation. Wild-type SOD1 and human mSOD1 associate with mitochondria [468,469]. Human SOD1 mutants associate with spinal cord mitochondria in mSOD1 mice and can bind Bcl-2 [470,471], thus potentially being decoys or dominant negative regulators of cell survival molecules (Figure 1, Table 1), but it is not known if this process is occurring specifically in motor neurons. Binding of mSOD1 (and perhaps its low-mobility species) to mitochondria has been reported to be spinal cord-selective and age-dependent [472], but this work also lacks cellular resolution. A recent biochemical in vitro study has shown that endogenous SOD1 in the mitochondrial intermembrane space controls cytochrome c-catalyzed peroxidation and that G93A-mSOD1 mediates greater ROS production in the intermembrane space compared to wild-type SOD1 [473]. Human SOD1 mutants can also shift mitochondrial redox potential when expressed in cultured cells [447]. Nevertheless, the direct links between the physicochemical changes in wild-type and mutant SOD1 and the mitochondrial functional and structural changes associated with ALS and motor neuron degeneration remain uncertain.\nEM studies of motor neurons in G93Ahigh mice have shown that the OMM remains relatively intact to permit formation of mega-mitochondria [81,381]. Moreover, early in the disease of these mice, mitochondria in dendrites in spinal cord ventral horn undergo extensive cristae and matrix remodeling, while few mitochondria in motor neuron cell bodies show major structural changes [81]. Thus, the disease might start distally in mitochondria of the motor neuron processes [81,381]. Another interpretation of ultrastructural findings is that the mSOD1 causes mitochondrial degeneration by inducing OMM extension and leakage and intermembrane space expansion [474]. Mechanisms for this damage could be related to mSOD1 gaining access to the mitochondrial intermembrane space [473,474]. This mitochondrial conformation seen by EM might favor the formation of the mPTP (Figure 1); indeed, evidence for increased contact sites between the OMM and IMM in dendritic mitochondria in G93Ahigh mice has been found [81]. Another feature of motor neurons in young G93Ahigh mice, before symptoms emerge, is apparent fission of ultrastructurally normal mitochondria in cell bodies and fragmentation of abnormal mitochondria [81]. It is not clear if the cristae and matrix remodeling and the apparent fragmentation and fission mitochondria are related or independent events and if these abnormalities interfere with mitochondrial trafficking; nevertheless, morphological observations enforce the idea that mitochondria could be important to the pathobiology of mSOD1 toxicity to motor neurons in G93Ahigh mice.\nThe possibility of changes in mitochondrial trafficking in motor neurons of mSOD1 mice is mostly unexplored. Some data support the novel idea that mitochondria might act as messengers from distal regions of motor neurons in mSOD1 mice [5]. G93Ahigh-mSOD1 mouse motor neurons accumulate mitochondria from the axon terminals and generate higher levels of O2•-, •NO, and ONOO- than motor neurons in tg mice expressing human wild-type SOD1 [381]. This mitochondrial accumulation occurs at a time when motor neuron cell body volume is increasing, suggestive of ongoing abnormalities with ATP production or plasma membrane Na+,K+ ATPase [381]. G93A-mSOD1 perturbs anterograde axonal transport of mitochondria in cultured primary embryonic motor neurons [475] making it possible that retrogradely transported mitochondria with toxic properties from the neuromuscular junction fail to be returned to distal processes [5,381]. Mitochondria with enhanced toxic potential from distal axons and terminals could therefore have a “Trojan horse” role in triggering degeneration of motor neurons in ALS via retrograde transport from diseased skeletal muscle.\nMotor neurons in G93Ahigh-mSOD1 mice also accumulate higher levels of intracellular Ca2+ than motor neurons in human wild-type SOD1 tg mice [381]. The intracellular Ca2+ signal in motor neurons is very compartmental and mitochondrial-like in its appearance [188,381]. Abnormal elevations intracellular Ca2+ in G93Ahigh-mSOD1 mouse motor neurons have been seen also by different Ca2+ detection methods [476,477]. Recent work on a mouse neuromuscular junction preparation has shown that mitochondrial Ca2+ accumulation is accompanied by greater IMM depolarization, specifically within motor neuron terminals of human mutant SOD1 tg mice [478].\nNO signaling mechanisms in mitochondria (Figure 1) of ALS mice appear to be involved in the pathogenesis. Motor neurons seem to be unique regarding NO production because they express constitutively low levels of inducible NO synthase (iNOS) [188,381,402]. G93Ahigh-mSOD1 mouse motor neurons accumulate nicotinamide adenine dinucleotide phosphate diaphorase and iNOS-like immunoreactivity [381,402]. iNOS is also up-regulated aberrantly in human sporadic ALS motor neurons [479]. iNOS gene knockout [381] and iNOS inhibition with 1400W [402] extend significantly the lifespan of G93Ahigh-mSOD1 mice. Thus, mitochondrial oxidative stress, Ca2+ dysregulation, iNOS activation, protein nitration, and protein aggregation (not necessarily SOD1 though) are all likely intrinsic, cell automonous mechanisms in the process of motor neuron degeneration caused by mSOD1 in mice [381]. The mechanistic basis for the differences between human ALS and mSOD1 mice, regarding cell death phenotype [19,439], is not yet clear, but could be related to the extreme non-physiological expression of toxic mSOD1 or to fundamental differences in cell death mechanisms in human and mouse neurons [439] or tissue inflammation that drive motor neurons in mSOD1 tg mice to necrotic-like death according to the cell death matrix (Figure 2). Another contributing factor for this difference between human and mouse motor neurons is that mitochondria are functionally diverse and have species-specific activities and molecular compositions, including the makeup of the mPTP [480]. These possibilities allow for skepticism regarding the suitability of existing tg mSOD1 mouse lines to model human ALS.\n\nThe mPTP Contributes to the Disease Mechanisms of ALS in Mice\nDespite the implication of toxic effects of mSOD1 on mitochondria in mouse ALS, cause-effect relationships between abnormal functioning of mitochondria and initiation and progression of disease have been uncertain. These relationships need to be known because this knowledge could lead to new mechanism-based treatments for ALS. One specific target of investigation for mitochondria in disease causality is the mPTP (Figure 1).\nThe mPTP was first implicated in ALS pathogenesis using pharmacological approaches. Cyclopsorine A treatment of G93Ahigh mice, delivered intracerebroventricularly or systemically to mice on a multiple drug resistance type 1a/b background, improved outcome modestly [481,482,483]. These studies were confounded by the immunosuppressant actions of cyclopsorine A through calcineurin inhibition. Pharmacological studies using CyPD inhibitors devoid of effects on calcineurin need to be done on ALS mice. Another study showed that treatment with cholest-4-en-3-one oxime (TRO19622), a drug that binds VDAC and the 18 kDa translocator protein (TSPO, or peripheral benzodiazepine receptor), improved motor performance, delayed disease onset, and extended survival of G93Ahigh mice [484]. However, another study using a different TSPO ligand (Ro-4864) did not show positive effects with G93Ahigh mice [485].\nCyPD and ANT are targets of nitration in ALS mice (Figure 1) [81]. CyPD nitration is elevated in early- to mid-symptomatic stages, but declines to baseline at end-stage disease [81]. ANT nitration is pertinent because it occurs in pre-symptomatic and symptomatic stages but not at end-stage disease or in tg mice expressing human wild-type SOD1 [81]. The ANT is important in the context of age-related neurodegenerative disease because it undergoes carbonyl modification during normal aging in housefly flight muscle [486] and rat brain [487]. In vitro cell-free and cell experiments have shown that NO and ONOO- can act directly on the ANT to induce mitochondrial permeabilization in a cyclosporine A-sensitive manner [488]. Oxidative stress enhances the binding of CyPD to ANT [489]. Some SOD1 mutants are unstable and lose copper [464,465], and interestingly, copper interactions with ANT and thiol modification of ANT can cause mPTP opening [490,491]. Together these data and future work could reveal that oxidative and nitrative damage to proteins, some of which are core components of the mPTP, in G93Ahigh mice is targeted rather than stochastic and could impinge on the functioning of the mPTP.\nThe role of CyPD in the process of motor neuron disease in ALS mice has been examined through gene-ablation [81]. G93Ahigh-mSOD1 mice without CyPD show markedly delayed disease onset and lived significantly longer than tg mice with CyPD. The effect of CyPD deletion was much more prominent in females than in males [81]. Remarkably, female mice showed positive effects with only haplo-deletion of CyPD. Ppif gene ablation in tg mice with much lower levels of human mSOD1 expression and a slower disease progression (G93Alow-mSOD1 mice) also show significantly delayed disease onset and lived significantly longer than tg mice with CyPD [81]. Thus, some form of mPTP pathobiology is occurring regardless of whether transgene expression of G93A is high or low.\nNevertheless, most G93A-mSOD1 mice without CyPD develop eventually motor neuron disease and die. Other work on CypD null mice has shown that high concentrations of Ca2+ (2 mM) can still lead to mPTP activation without CyPD and that cell deaths caused by Bid, Bax, DNA damage and TNF still occur without CyPD [492]. The effects of CyPD deficiency on motor neuron cell mechanisms thus need detailed examination, but the cell death phenotype might switch or convert to another form with the attenuation of mitochondrial swelling. A switch in the cell death morphology and molecular mechanisms in motor neurons of mSOD1 mice without CyPD is an outcome consistent with the cell death matrix concept (Figure 2) [194]."}