Wild-type Cu/Zn superoxide dismutase (SOD1) does not facilitate, but impedes the formation of protein aggregates of amyotrophic lateral sclerosis causing mutant SOD1

作者：Witan Heidrun; Gorlovoy Philipp; Kaya Ali M; Koziollek Drechsler Ingrid; Neumann Harald; Behl Christian^*; Clement Albrecht M

来源：Neurobiology of Disease, 2009, 36(2): 331-342.

DOI：10.1016/j.nbd.2009.07.024

• Amyotrophic lateral sclerosis
• Heterodimerization
• Protein aggregation
• FLIM-based FRET

Aggregation of Cu/Zn superoxide dismutase (SOD1) is a hallmark of a subset of familial amyotrophic lateral sclerosis (ALS) cases. The expression of wild-type SOD1 [SOD(hWT)] surprisingly exacerbates the phenotype of mutant SOD1 in vivo. Here we studied whether SOD1(hWT) may affect mutant SOD1 aggregation by employing fluorescence microscopy techniques combined with lifetime-based Forster resonance energy transfer (FRET). Only a very minor fraction of SOD1 (hWT) was observed in aggregates induced by mutant SOD1(G37R), SOD1(G85R) or SOD1(G93C). Quite in contrast, co-expression of SOD(hWT) reduced the amount of mutant SOD1 in the aggregate fraction. Furthermore, we did not detect endogenous mouse SOD1 in aggregates formed by mutant SOD1 in two distinct mutant SOD1 mouse lines. The hypothesis that SOD1 (WT) is able to keep mutant SOD1 variants in a soluble state is supported by the increased presence of heterodimers upon SOD1 (hWT) co-expression. Therefore we propose that SOD1 (WT) contributes to disease by heterodimerization with mutant SOD1 forms.

• 出版日期2009-11