Scientists from UK and Taiwan have developed a modeling platform at the cellular level, which summarizes the key aspects of sporadic ALS and demonstrates both an initial neuroprotective role for astrocytes and the cell-type specific toxic effect of TDP-43 oligomers.
A key pathological feature of ALS is the cytoplasmically poorly located and aggregated TDP-43 protein in at least 95% of cases. Research on ALS has spanned more than 20 years, primarily focused on the genetic aspects of ALS, which however only account for approximately 10% of cases. This has the remaining 90% of sporadic ALS cases relatively little studied. In addition, and despite considerable investment in genetic research, the most common gene for ALS (C9orf72) was only discovered in 2011.
The role of non-neuronal cells (glial cells) has also been neglected for a very long time. First because we thought that their role was limited to metabolism and the maintenance of synapses, then because it is much easier to understand what little use a neuron which often connects two distant points of the nervous system, only cells that only seem to have a local role. Today we know that these cells are as important as neurons for mental processes, and that microglia play the role of the immune system in the nervous system. Among these cells are astrocytes and their relationship with the TDP-43 pathology is not yet well understood at present.
The authors of the study that is the subject of this post therefore used motor neurons and astrocytes derived from human-induced pluripotent stem cells (iPSC) to model the specific characteristics of motor neurons in sporadic ALS.
The authors exposed its human iPSC-derived motor neurons to tissue extracts from sporadic ALS patients and observed that the TDP-43 protein aggregated in the cytoplasm of these motor neurons. Contrary to what had been achieved in previous studies, aggregation was obtained with very low concentrations of TDP-43. We can therefore speak of seeding, a characteristic of prion diseases.
Next, the authors showed that motor neurons derived from human iPSC are more vulnerable to the aggregation and toxicity of TDP-43 than their astrocyte counterparts. These TDP-43 aggregates can spread from motor neurons to astrocytes. The authors, however, discovered that astrocytes are capable of reducing poorly localized cytoplasmic TDP-43 and cell toxicity.
In summary, these scientists detected TDP-43 oligomers in these spALS spinal cord extracts, and demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this specific cell-type toxicity, providing additional support for a hypothesis of mediated toxicity. by protein oligomers in ALS, i.e. prion-like behavior.
