Protein Misdirection Inside and Outside Motor Neurons in Amyotrophic Lateral Sclerosis (ALS): A Possible Clue for Therapeutic Strategies

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

Histomorphometric analysis of secondary cancellous bones in vertebral body.

<p>(A) Representative micrographs of sagittal sections of vertebral bodies stained with Villanueva bone staining without decalcifying treatment are shown. (B) Histomorphometrical parameters (BV/TV, bone volume/tissue volume; ES/BS, eroded surface/bone surface; OV/OS, osteoid volume/osteoid surface; O.Th, osteoid thickness; MAR, mineral apposition rate; N.Mo.Oc/BS, number of mononuclear osteoclast/bone surface; N.Mu.Oc/BS, number of multinuclear osteoclast/bone surface; and N.Ob/BS, number of osteoblast/bone surface) of secondary spongiosa in vertebral bodies are shown. Data are presented as mean ± standard error of the mean. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. sham rat group; ^†P < 0.05, ^††P < 0.01, and ^†††P < 0.001 vs. normal rat control group.</p

Histomorphometric analysis of secondary cancellous bones in distal femur metaphysis.

<p>(A) Representative micrographs of slices of frontal section of distal femur stained with Villanueva bone staining without decalcifying treatment are shown. (B) Histomorphometrical parameters (BV/TV, bone volume/tissue volume; ES/BS, eroded surface/bone surface; OV/OS, osteoid volume/osteoid surface; O.Th, osteoid thickness; MAR, mineral apposition rate; N.Mo.Oc/BS, number of mononuclear osteoclast/bone surface; N.Mu.Oc/BS, number of multinuclear osteoclast/bone surface; and N.Ob/BS, number of osteoblast/bone surface) of secondary cancellous bones in distal femur metaphysis are shown. Data are presented as mean ± standard error of the mean. ***P < 0.001 vs. sham rat group; ^†††P < 0.001 vs. normal rat control group.</p

Micro-CT analysis of trabecular bone in vertebral body.

<p>(A) Representative 3-dimensional micro-CT images of trabecular bones in vertebral bodies are shown. (B) Microstructural parameters (BV/TV, trabecular bone volume fraction; Tb.N, trabecular number; Tb.SP, trabecular separation; Conn.D, connectivity density; DA, degree of anisotriphy) of trabecular bones in vertebral bodies are shown. Data are presented as mean ± standard error of the mean. ***P < 0.001 vs. sham rat group.</p

Micro-CT analysis of trabecular bones in distal femur metaphysis.

<p>(A) Representative 3-dimensional micro-CT images of trabecular bones in distal femur metaphysis are shown. (B) Microstructural parameters (BV/TV, trabecular bone volume fraction; Tb.N, trabecular number; Tb.SP, trabecular separation; Conn.D, connectivity density; DA, degree of anisotriphy) of trabecular bones in distal femur metaphysis are shown. Data are presented as mean ± standard error of the mean. **P < 0.01, ***P < 0.001 vs. sham rat group.</p

Composition of a αT-deficient diet.

<p>αT: α-tocopherol</p><p>Composition of a αT-deficient diet.</p