Poor SOD

There has been a question whether SOD1 plays a part in sporadic ALS (SALS) as well as familial ALS (FALS), in which one of a large number of inherited defects in the SOD1 gene cause alterations (misfolding) of the SOD1 enzyme which it encodes. A recent study published in PLoS ONE suggests that misfolded SOD1 is present in all cases of ALS, not just in those involving genetic defect. Some previous studies have had similar results while others have not. Apparently this study used a fairly aggressive set of antibodies to detect inclusions (flaws) in the motor neurons which consisted of SOD1. Whether the misfolded SOD1 or the inclusions/aggregates that result are the cause of disease is still being questioned, although disease effects can be seen prior to visible aggregates forming. Two things about this study I found interesting: First, the study reported that the inclusions were found mostly in the axon hillock which makes me wonder if this can be related to the slowing of axonal transport which is a very early event in ALS. Second, if you look at the diagram in the SOD1 link above, you can see that it is a rather tight and highly complicated enzyme to fold. A mutation may make it more difficult or impossible for a lysosome to break down. Lysosomes are rather important cellular components. The subject study indicates that the misfolded SOD1 found in the motor neurons co-localized with lysosomes, suggesting that the lysosomes were choking on the mutant enzymes. Lysosomal dysfunction has already been linked to several diseases, including neurological. It is known that lysosomal function degrades with age, and ALS is an age-related disease (both SALS and FALS begin after decades of otherwise normal life). At least one study is being conducted, attempting to address ALS by means of increasing lysosomal function. Of course, this assumes a "neurocentric" view of the disease, where the pathogenesis is in the neuron itself. Recent research suggests this may not be the case, and that some upstream event triggers the cascade that leads to distress and death of the motor neurons. It is this "missing link" that continues to confound researchers.