Filézac de L'Etang A, Maharjan N, Cordeiro Braña M, Ruegsegger C, Rehmann R, Goswami A, Roos A, Troost D, Schneider BL, Weis J, Saxena S. Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS. Nat Neurosci. 2015 Feb;18(2):227-38. Epub 2015 Jan 5 PubMed.
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Comments
This is a provocative paper that follows on from the observation that the unfolded protein response of the endoplasmic reticulum (ER) becomes activated in a fraction of motor neurons at a point in the progression of some forms of ALS. At the circuit level, the idea of selective expression of Sil1 in specific motor neuron firing types (slow-firing), and also of other components (MMP9 was reported in fast-firing MNs), emphasizes our need to understand what it is that makes FF motor neurons selectively vulnerable. It may be a multiplicity of factors. Whatever the reason, it seems like overexpression of Sil1 increases longevity of SOD G93A animals.
While we would agree that fast-firing motor neurons are the vulnerable ones (see Hadzipasic et al., 2014), we see no ER stress in the G85R SOD1YFP model in motor neurons (Bandyopadhyay et al, 2013), but investigators studying G93A always seem to see evidence of ER stress. I wonder if it might be secondary to having free metals fall off of G93A, since the protein is constantly folding and unfolding. Under the electron microscope, membranes in G93A seem damaged, perhaps due to free radicals, whereas in G85R (which never folds and does not appear to take on metals) the organellar and other membranes look intact. I worry that ER stress is not a primary and consistent ALS-related pathology, or at least the G85R SOD1YFP fusion animals do not require it in order to go on to paralysis. Nonetheless, this study seems to have a fair-sized effect on survival of G93A by altering Sil1.
Mechanistically, one could understand that overexpression of this nucleotide exchanger of BiP at the cellular level might enhance BiP actions to improve ER quality control and overall cell health. But how that might decrease misfolding of what is mostly, if not entirely, cytosolic mutant SOD1 seems elusive. Nevertheless, Sil1 might be of benefit in these situations.
References:
Hadzipasic M, Tahvildari B, Nagy M, Bian M, Horwich AL, McCormick DA. Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16883-8. Epub 2014 Nov 10 PubMed.
Bandyopadhyay U, Cotney J, Nagy M, Oh S, Leng J, Mahajan M, Mane S, Fenton WA, Noonan JP, Horwich AL. RNA-Seq profiling of spinal cord motor neurons from a presymptomatic SOD1 ALS mouse. PLoS One. 2013;8(1):e53575. PubMed.
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