Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form |
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Authors: | Aaron Kerman Hsueh-Ning Liu Sidney Croul Juan Bilbao Ekaterina Rogaeva Lorne Zinman Janice Robertson Avijit Chakrabartty |
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Institution: | (1) Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, TMDT 4-305, 101 College Street, Toronto, ON, M5G 1L7, Canada;(2) Department of and Biochemistry, Ontario Cancer Institute, University of Toronto, TMDT 4-305, 101 College Street, Toronto, ON, M5G 1L7, Canada;(3) Department of Laboratory Medicine and Pathobiology, Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Cres. W., Toronto, ON, M5S 3H2, Canada;(4) Department of Laboratory Medicine and Pathobiology, UHN Path 11E426 Toronto General Hospital, University of Toronto, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada;(5) Sunnybrook Health Sciences Centre, Toronto, ON, Canada; |
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Abstract: | Amyotrophic lateral sclerosis (ALS) is a conformational disease in which misfolding and aggregation of proteins such as SOD1
(familial ALS) and TDP-43 (sporadic ALS) are central features. The conformations adopted by such proteins within motor neurons
in affected patients are not well known. We have developed a novel conformation-specific antibody (USOD) targeted against
SOD1 residues 42–48 that specifically recognizes SOD1 in which the beta barrel is unfolded. Use of this antibody, in conjunction
with the previously described SEDI antibody that recognizes the SOD1 dimer interface, allows a detailed investigation of the
in vivo conformation of SOD1 at the residue-specific level. USOD and SEDI immunohistochemistry of spinal cord sections from
ALS cases resulting from SOD1 mutations (A4V and ΔG27/P28) shows that inclusions within remaining motor neurons contain SOD1
with both an unfolded beta barrel and a disrupted dimer interface. Misfolded SOD1 can also be immunoprecipitated from spinal
cord extracts of these cases using USOD. However, in ten cases of sporadic ALS, misfolded SOD1 is not detected by either immunohistochemistry
or immunoprecipitation. Using the amyloid-specific dyes, Congo Red and Thioflavin S, we find that SOD1-positive inclusions
in familial ALS, as well as TDP-43- and ubiquitin-positive inclusions in sporadic ALS, contain non-amyloid protein deposits.
We conclude that SOD1 misfolding is not a feature of sporadic ALS, and that both SOD1-ALS and sporadic ALS, rather than being
amyloid diseases, are conformational diseases that involve amorphous aggregation of misfolded protein. This knowledge will
provide new insights into subcellular events that cause misfolding, aggregation and toxicity. |
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