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Selective uptake of C-terminal fragments of TDP-43 into exosome

  • P2-311
  • 阿部 圭輔 / Keisuke Abe:1 生田目 拓 / Taku Namatame:1 田尻 美緒 / Mio Tajiri:1 由井 大錦 / Daishi Yui:1 大久保 卓哉 / Takuya Ohkubo:1 横田 隆徳 / Takanori Yokota:1 
  • 1:東京医科歯科大学 / Tokyo Medical and Dental University 

Cytoplasmic mislocalization and various type of inclusions of TAR DNA-binding protein 43 kDa (TDP-43) are seen in motor neurons in Amyotrophic lateral sclerosis (ALS) patients , which is related to motor neuron death. By our previous review of ALS pathology, it is considered that TDP-43 pathology might spread by contiguous and non-contiguous propagation. In non-contiguous propagation, two possible mechanisms are supposed to be existed, that are trans-synaptic spread among neural networks and non-synaptic remote spread. We propose a hypothesis that the full-length or the toxic fragments of wild-type TDP-43 might become incorporated into exosome and they spread in blood and/or cerebrospinal fluid (CSF) ,which will cause TDP-43 pathology propagation.
We prepared culture cells expressing full-length and C-terminal fragment of TDP-43, extracted exosome from cell lysates and then fractionated into sarkosyl soluble and sarkosyl insoluble fractions. Immunoblot analyses revealed that overexpressed full-length TDP-43 in Neuro2a cells was not only phosphorylated but also fragmented in cell lysates. On the other hand, in exosome fraction, there are few amount of full-length TDP-43 and, 25kDa and 30kDa C-terminal fragments (CTFs) of TDP-43 were selectively incorporated and mostly existed in sarcosyl insoluble fraction.
TDP-43 proteinopathy including ALS is known to be classified into four types which are characterized by the immunoblot band patterns of insoluble 25kDa CTFs of TDP-43. We suppose that the insoluble CTFs of TDP-43 in exosome is related to non-contiguous distribution of TDP-43 pathology.

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