One of the mysteries of inherited neurodegenerative diseases is how ubiquitously expressed mutant proteins can selectively target specific sets of neurons for cell death. Two studies recently published in Neuron now shed light on how mutations in Cu/Zn superoxide dismutase (SOD1), a normally protective protein, cause selective death of motor neurons in some cases of familial amyotrophic lateral sclerosis (ALS).

Using a series of SOD1 mouse mutants, and tissue samples from patients with familial ALS, Liu et al. showed that various disease-related mutants of SOD1, but not wild-type SOD1, collected in the mitochondria of affected tissue. Specifically, mutant SOD1 preferentially associated with membrane proteins in spinal cord mitochondria, but not in the mitochondria of unaffected tissues such as muscle or liver. This build up of SOD1 in mitochondria occured at around the time of the earliest pathology and before disease onset.

The authors propose that the spinal cord mitochondrial cells are singled out probably because of an as-yet undiscovered import mechanism in these cells that causes them to recognize mutant SOD1 as a substrate for selective import. They suggest that this selective association initiates a cascade of damage, whereby SOD1 blocks the mitochondrial membranes, preventing import of necessary substances, and some even enters the mitochondria, disrupting their normal activity.

The mechanism by which SOD1 destroys spinal cord neurons once it reaches the mitochondria was the focus of the study by Pasinelli et al. They showed that wild-type and mutant SOD1 interact specifically with the protein B-cell leukaemia/lymphoma-2 (BCL2) — a protein that resides on the outer surface of the mitochondrial membrane and normally suppresses cell death — both in vitro and in vivo in human and mouse spinal cord. The authors went on to show that BCL2 binds to mutant SOD1-containing aggregates in mitochondria in the spinal cord but not in the liver, consistent with the findings of Liu et al. So, it seems that mutant SOD1 interacts with the mitochondria by binding with BCL2, which in turn leads to accelerated cell death. The mechanisms for this are unclear, but might be related to the mutant protein being positioned in a way that is toxic to the mitochondria. The authors also suggest that because SOD1-containing aggregates trap significant amounts of BCL2, this might trigger the cell-death machinery by either depleting BCL2 or rendering it non-functional, which could then make the mitochondria and its host cell less viable. It is also important to note that BCL2 is necessary for maintaining mitochondrial membrane potential, indicating another possible route for the destructive actions of SOD1 on motor neurons.

So, together, these two studies take us a step closer to understanding the mechanisms that lead to a compromise in motor neuron viability in ALS. But, as they point out, further work is needed to delineate the particular spinal cord factors that facilitate the association between SOD1 and mitochondrial membrane proteins.