Extremos condicionados

The mechanisms involved in the selective motor neuron degeneration caused by SOD1 mutations in ALS remain unresolved, however, a plethora of hypotheses have been proposed (Ilieva et al. 2009; Rothstein, 2009). In this section, I summarise the current aspects of the pathogenesis of SOD1-linked ALS that may be particularly relevant to DM, including oxidative damage (Barber et al. 2006; Kabashi et al. 2007), protein misfolding and aggregation (Watanabe et al. 2001), mitochondrial dysfunction (Israelson et al. 2010) and non-cell autonomous motor neuron death.

The SOD1 enzymes are directly associated with the cellular antioxidant defence mechanism that are involved in catalysing the toxic superoxide radicals (Bannister et al. 1991). The global distribution of SOD1 mutations across all exons therefore intuitively suggests the loss of SOD1 function and hypothesises accumulation of free radicals and oxidative stress that eventually leads to motor neuron death in ALS (Deng et al. 1993). However, homozygote SOD1 knockout murine models reported in previous studies have failed to develop apparent motor neuron signs (Reaume et al. 1996; Ho et al. 1998), while transgenic murine models over-expressing mutant human SOD1 (G93A, G85R and H46R) do produce motor neuron degeneration and paralysis despite normal endogenous SOD1

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activity (Gurney et al. 1994; Bruijn et al. 1997; Nagai et al. 2001). These observations lead to the proposition that motor neuron death in SOD1-linked ALS reflects acquired toxic properties of the mutant SOD1 protein rather than loss of function (Nagai et al. 2001; Rothstein, 2009). However, despite strong evidence of the gain of toxic SOD1 function in ALS pathogenesis, the hypothesis of the loss of function cannot be completely excluded (Turner and Talbot, 2008). More recent evidence has demonstrated that the SOD1 knockouts display multisystem abnormalities (Ho et al. 1998; Imamura et al. 2006; Elchuri et al. 2005) including significant locomotor deficits associated with peripheral axonopathy (Muller et al. 2006; Fischer and Glass, 2007). It remains unclear why SOD1 knockouts do not display distinctive motor neuron signs in earlier studies, however such a response is potentially caused by compensatory mechanisms that are yet to be discovered (Turner and Talbot, 2008).

The putative toxic gain of SOD1 protein mechanisms that induce motor neuron degeneration in ALS remains unknown, but may involve several complex interacting molecular pathways (Rothstein, 2009). The individual SOD1 mutations are scattered throughout the protein, which are predicted to interfere with different aspects of the protein structure depending on the location of the mutation (Valentine et al. 2005). This contributes to failure of the protein to fold properly leading to accumulation of misfolded SOD1 proteins and SOD1 aggregates or inclusion formation in motor neurons as observed in ALS patients (Bruijn et al. 1997; Watanabe et al. 2001). The accumulation of misfolded SOD1 protein subsequently activates the unfolded protein response (UPR), which is a quality control of cellular mechanisms that facilitate protein folding (Bento- Abreu et al. 2010). A potential cascade involves the accumulation of misfolded SOD1 within the ER, inducing ER stress. ER stress initiates the upregulation of a number of UPR enzymes and chaperones (e.g., PDI, BiP) as well as transcription factors (e.g., ATF6, XBPI) that alter protein translation rates (Atkin et al. 2006; Atkin et al. 2008). The clearance of misfolded SOD1 proteins can be mediated by the ubiquitin-proteosome pathway but there is evidence that this system may be disrupted in ALS (Urushitani et al. 2002). Collectively, these events may lead to motor neuron death.

Misfolded SOD1 proteins have been associated with mitochondrial perturbations by the aberrant deposition of the misfolded SOD1 proteins in the outer membrane of mitochondria (Vande et al. 2008). There is a clear implication that misfolded SOD1 proteins could bind directly to the voltage-dependent anion channel 1 protein (VDAC1)

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(Israelson et al. 2010), which is embedded in the outer mitochondrial membrane that regulates metabolite exchange (eg., adenosine triphosphate and adenine nucleotides) and the release of reactive oxygen species (ROS) between mitochondria and cytosol (Han et al. 2003; Colombini, 2004). Therefore, the binding of misfolded SOD1-VDAC1 would disrupt the metabolite flux and the release of ROS from the mitochondria, leading to oxidative stress and mitochondrial dysfunction (Israelson et al. 2010). Such dysfunction can eventually induce morphological damage to mitochondria and activate apoptosis cascade events (Pedrini et al. 2010).

In addition to the potential mechanisms described above there is evidence to support a non- cell autonomous contribution to the viability of motor neurons in ALS (Ilieva et al. 2009). Transgenic mice expressing mutant SOD1 in motor neurons with wild type SOD1 in non- neuronal cells are not sufficient to induce ALS, which clearly implies that the non-neuronal cells may substantially contribute to the disease initiation (Clement et al. 2003; Yamanaka et al. 2008). The exact mechanism of a non-cell autonomous affect in ALS has not been fully delineated although a hypothesis has been proposed on the formation of misfolded SOD1 aggregates in the neighbouring glial cells; astrocytes and microglia that could subsequently trigger a series of neurotoxic factors including inflammatory cytokines and ROS, which potentially exacerbates the damage to the motor neurons (Harraz et al. 2008; Ilieva et al. 2009). The involvement of other non-neuronal cells such as Schwann cells (Lobsiger et al. 2009) and T-lymphocytes (Beers et al. 2008; Chiu et al. 2008) have also been implicated in ALS onset and progression.

The initial damage in ALS may take place within motor neurons however the involvement of non-neuronal cells may also directly contribute to the development of ALS pathology (Ilieva et al. 2009). Therefore, all proposed mechanisms, either loss or gain of function, are probably contributors to ALS pathogenesis through induction of damage within different cell types (Pasinelli and Brown, 2006; Turner and Talbot, 2008), although it remains to be established whether these mechanisms are involved in DM pathogenesis. The selective vulnerability of motor neurons in ALS with mutant SOD1 remains unexplained, although it may be related to the requirements needed to maintain long motor axons and the high energy demand of the cargo proteins involved in retro- and anterograde transport (Shaw and Eggett, 2000). Although the precise mechanisms remain unresolved, it is clear that motor neurons are very sensitive to oxidative stress and mitochondrial

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dysfunction, and this may increase the vulnerability of these cells compared to others (Robberecht et al. 2000).