Differential involvement of optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations

Abstract

Background: Mutations in optineurin have recently been linked to amyotrophic lateral sclerosis (ALS).

Objective: To determine whether optineurin-positive skeinlike inclusions are a common pathologic feature in ALS, including SOD1 -linked ALS.

Design: Clinical case series.

Setting: Academic referral center.

Subjects: We analyzed spinal cord sections from 46 clinically and pathologically diagnosed ALS cases and ALS transgenic mouse models overexpressing ALS-linked SOD1 mutations G93A or L126Z.

Results: We observed optineurin-immunoreactive skeinlike inclusions in all the sporadic ALS and familial ALS cases without SOD1 mutation, but not in cases with SOD1 mutations or in transgenic mice overexpressing the ALS-linked SOD1 mutations G93A or L126Z.

Conclusion: The data from this study provide evidence that optineurin is involved in the pathogenesis of sporadic ALS and non- SOD1 familial ALS, thus supporting the hypothesis that these forms of ALS share a pathway that is distinct from that of SOD1-linked ALS.

Figures

Figure 1

Optineurin (OPTN)-immunoreactive inclusions in amyotrophic lateral sclerosis (ALS). Representative OPTN-immunoreactive inclusions were detected by antibody C-term in sporadic ALS (SALS) (A–C and F) and non-SOD1 familial ALS (FALS) (D and E). The typical skeinlike inclusions in soma and neurites are shown by small arrows and arrowheads, respectively. Some inclusions appeared to be compact (large arrowhead in panel F). Representative Bunina bodies (large arrow in panel G) stained with hematoxylin and eosin (H&E) were destained, then restained with OPTN antibody and were negative for OPTN (H).

Figure 2

Immunoreactivity of optineurin in ubiquitin-positive inclusions in sporadic amyotrophic lateral sclerosis (SALS) cases, SOD1-linked ALS, and SOD1 transgenic (Tg) mice. Confocal microscopy was performed using antibodies to optineurin (green) and ubiquitin (red) on the spinal cord sections from ALS cases and Tg mice. Representative images show that the ubiquitin-positive inclusions are optineurin-positive in SALS cases (A–C), but negative in SOD1-G85R (D–F) and SOD1-A4V (G–I), as well as in ALS Tg mice overexpressing SOD1-G93A ( J–L) or SOD1-L126Z (M–O). Representative optineurin-positive skeinlike inclusions in an SALS case are indicated by arrows in panel A. The ubiquitin-positive inclusions in soma and neurites are indicated by arrows and arrowheads, respectively, in panels B, E, H, K, and N.

Figure 3

Schematic model depicting 2 parallel pathways involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). TDP-43, FUS, and optineurin are components of pathologic inclusions in sporadic ALS (SALS) and SOD1-negative familial ALS (FALS). SOD1-positive inclusions are exclusively present in SOD1-linked FALS. Ubiquitin and p62 may represent a common pathway involved in the formation of skeinlike inclusions, eventually leading to motor neuron degeneration.