The Science article by Clement (Don Cleveland, University of California) and other US and Canadian researchers is a masterpiece in demonstrating the prominent influence of non-neuronal cells on the ALS pathogenesis, which can be extrapolated to other neurodegenerative diseases. I take this opportunity to add a piece of evidence we observed indicating phenotypic changes within astrocytes located in the vicinity of the axons belonging to damaged (and dying) motoneurons from both SOD1 transgenic mice model and human sporadic ALS (see ref. below).

References:
Hoyaux D, Boom A, Van den Bosch L, Belot N, Martin JJ, Heizmann CW, Kiss R, Pochet R. S100A6 overexpression within astrocytes associated with impaired axons from both ALS mouse model and human patients, J Neuropathol Exp Neurol. 2002 Aug;61(8):736-44. Abstract

View all comments by Roland Pochet

Astrocytes in brain as a form of extracellular matrix. As evolution proceeded, animals developed more astrocytes relative to neurons. Annelids have equal numbers, monkeys already have more astrocytes than neurons, humans 3 times more. We need more investigations of astrocytes in brain diseases. I predict that astrocytes will be the cells of 21 century.

View all comments by Soraya Valles

In light of the ongoing efforts to downregulate SOD1 via various RNA interference approaches, the recent paper by Lobsiger and colleagues has particular significance. It poignantly reminds us that not all “mutant” SOD1 is toxic—but rather some SOD1 seems to function in its intended capacity as an antioxidant enzyme. Furthermore, while we assume that all mutant SOD1-mediated toxicity must converge on a final common pathway resulting in motor neuron degeneration and ultimate death, the roads along the way might be slightly different.

In the report put forward by Lobsiger, the (efficient) removal of SOD1 from the peripheral Schwann cells yielded a very unexpected outcome—disease was accelerated. It has now been accepted that non-cell autonomous mechanisms must be at play in motor neuron degeneration, but the same is obviously true for motor neuron survival as well. Clearly, Schwann cells (which have the most intimate association with motor neurons, numbering 1000:1!) provide essential function for the maintenance of motor axons. Indeed, earlier work (Reaume et al., 1996)...  Read more

In light of the ongoing efforts to downregulate SOD1 via various RNA interference approaches, the recent paper by Lobsiger and colleagues has particular significance. It poignantly reminds us that not all “mutant” SOD1 is toxic—but rather some SOD1 seems to function in its intended capacity as an antioxidant enzyme. Furthermore, while we assume that all mutant SOD1-mediated toxicity must converge on a final common pathway resulting in motor neuron degeneration and ultimate death, the roads along the way might be slightly different.

In the report put forward by Lobsiger, the (efficient) removal of SOD1 from the peripheral Schwann cells yielded a very unexpected outcome—disease was accelerated. It has now been accepted that non-cell autonomous mechanisms must be at play in motor neuron degeneration, but the same is obviously true for motor neuron survival as well. Clearly, Schwann cells (which have the most intimate association with motor neurons, numbering 1000:1!) provide essential function for the maintenance of motor axons. Indeed, earlier work (Reaume et al., 1996) demonstrated that recovery from axonal injury was impaired in SOD1-/- mice. However, it was assumed that the lack of recovery was due to the lack of SOD1 action within the motor neuron. What is now evident from Lobsiger’s work is that location matters: SOD1 action within Schwann cells actively participates in axonal recovery and maintenance.

While future experiments using the mentioned floxed G85R mouse will be the direct test of this hypothesis, this is an opportunity for reflection in ALS. At present, multiple groups are focused on SOD1 RNA interference-based approaches to remove SOD1. What is clear is that care should be taken not to inadvertently downregulate the protective SOD1 in peripheral Schwann cells. In fact, perhaps efforts to simultaneously downregulate CNS-expressed SOD1 and upregulate Schwann cell SOD1 might be an ideal therapeutic strategy.

References:
Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood DG, Beal MF, Brown RH, Scott RW, Snider WD. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet. 1996 May;13(1):43-7. Abstract

View all comments by Christine Vande Velde