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Review
. 2011;12(10):6980-7003.
doi: 10.3390/ijms12106980. Epub 2011 Oct 19.

Protein misdirection inside and outside motor neurons in Amyotrophic Lateral Sclerosis (ALS): a possible clue for therapeutic strategies

Akemi Ido  1 , Hidenao Fukuyama, Makoto Urushitani
Affiliations
Review

Protein misdirection inside and outside motor neurons in Amyotrophic Lateral Sclerosis (ALS): a possible clue for therapeutic strategies

Akemi Ido et al. Int J Mol Sci. 2011.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively. The commonalities of the two proteins include a propensity to aggregate and acquire detrimental conformations through oligomerization, fragmentation, or post-translational modification that may drive abnormal subcellular localizations. Although SOD1 is a major cytosolic protein, mutated SOD1 has been localized to mitochondria, endoplasmic reticulum, and even the extracellular space. The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive. Nevertheless, these abnormal behaviors based on the protein misfolding are believed to induce diverse intracellular and extracellular events that may be tightly linked to non-cell-autonomous motor neuron death. The generation of mutant- or misfolded protein-specific antibodies would help to uncover the distribution and propagation of the ALS-linked proteins, and to design a therapeutic strategy to clear such species. Herein we review the literature regarding the mislocalization of ALS-linked proteins, especially mutant SOD1 and TDP-43 species, and discuss the rationale of molecular targeting strategies including immunotherapy.

Keywords: SOD1; TDP-43; antibody; non-cell-autonomous motor neuron death; seeding; subcellular localization.

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Figures

Figure 1
Figure 1
Aberrant subcellular localization of mutant SOD1 protein and the associated effect on ALS pathogenesis. Mutant SOD1 interacts with several “accompanying proteins”, resulting in the abnormal subcellular localization.
Figure 2
Figure 2
Fragments of TDP-43 and their effects on aggregate propensity or cytotoxicity. Black bars are reported to generate cytosolic aggregates or to induce cell death in vitro and in vivo. Grey bars were shown not to provide detrimental effects. Amino acid sequence and its source reference are indicated under each bar. References in square brackets are shown in the Reference section.
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