筋萎縮性側索硬化症病態におけるTDP–43

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  • The role of TDP–43 in ALS pathogenesis

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<p>TAR DNA–binding protein 43kDa (TDP–43) is a hallmark protein for amyotrophic lateral sclerosis (ALS), consisting of ubiquitinated and phosphorylated cytosolic inclusions in affected regions, namely TDP–43 proteinopathy. TDP–43 is physiologically located in the nucleus and plays diverse roles to maintain the RNA homeostasis, including pro–mRNA splicing, microRNA processing, non–coding RNA stabilization, mRNA transport, and the stress granule formation. Multiple cascades, basically causing a loss of these functions, have been proposed as TDP–43–linked ALS pathogenesis ; however, the mislocalization and aggregate formation of TDP–43 is considered to underlie various pathogenic pathways, ultimately leading to motor neuron death. A cell–to–cell spreading theory is attracting huge attention to explain the rapid regional progression of the paralysis, although in vivo evidence is still lacking. Recent knowledge highlights the stress granules as responsible sites of TDP–43 inclusion formation. The stress granules contain mRNA with chains of ribosomes, together with stress granule–related proteins, such as TIA1 and TDP–43, in which RNA translation is inhibited transiently until stress conditions are recovered. The disruption of this reversibility is implicated in the irreversible inclusion formation. A proportion of familial ALS patients carries genetic mutations in the TDP–43 gene, the most of which are concentrated at the carboxyl prion–like domain. Although the pathomechanisms regarding how mutant TDP–43 causes ALS remain elusive, it is reported that mutant TDP–43 impairs proteasome activity, resulting in the accumulation of aberrant TDP–43. Moreover, several genetic mutations other than TDP–43, such as C9ORF72, MATR3, hnRNP1, UBQLN2, STSM1, VCP, and OPTN cause TDP–43 proteinopathy. Importantly, transgenic mice expressing cytosolic TDP–43 show the similar phenotype of ALS, and the inhibition of the transgene restore the paralysis of the mice. These line of evidence indicate the huge potential of misfolded TDP–43 as a therapeutic target. Capturing the early structural conversion to pathogenic forms is a promising therapeutic avenue to overcome ALS.</p>

収録刊行物

  • 神経治療学

    神経治療学 34 (2), 72-78, 2017

    日本神経治療学会

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