Exogenous polyserine and polyleucine are toxic to recipient cells

Abstract

Repeat-associated non-AUG (RAN) translation of mRNAs/transcripts responsible for polyglutamine (polyQ) diseases may generate peptides containing different mono amino acid tracts such as polyserine (polyS) and polyleucine (polyL). The propagation of aggregated polyQ from one cell to another is also an intriguing feature of polyQ proteins. However, whether the RAN translation-related polyS and polyL have the ability to propagate remains unclear, and if they do, whether the exogenous polyS and polyL exert toxicity on the recipient cells is also not known yet. In the present study, we found that aggregated polyS and polyL peptides spontaneously enter neuron-like cells and astrocytes in vitro. Aggregated polyS led to the degeneration of the differentiated neuron-like cultured cells. Likewise, the two types of aggregates taken up by astrocytes induced aberrant differentiation and cell death in vitro. Furthermore, injection of each of the two types of aggregates into the ventricles of adult mice resulted in their behavioral changes. The polyS-injected mice showed extensive vacuolar degeneration in the brain. Thus, the RAN translation-related proteins containing polyS and polyL have the potential to propagate and the proteins generated by all polyQ diseases might exert universal toxicity in the recipient cells.

Conditioned medium from BV2 microglial cells having polyleucine specifically alters startle response in mice

“…Aggregated misfolded proteins such as HTT have the general ability to propagate between cells 23 . In line with this phenomenon, we reported that aggregated 13A, 13S and 13L entered PC12 cells and some of them changed their morphology 22 , 24 . Especially, microglial cells are expected to facilitate such propagation because microglial cells phagocytose cell debris and damaged neurons 25 .…”

“…1 c) inside the cells (Fig. 1 ) as seen in PC12 cells 22 , 24 . Ortho images of the XZ-axis cross section view verified that the 13A (Fig.…”

“…We recently showed that injection of 13S and 13L themselves into the lateral ventricle altered anxiety and depression or stress-coping behavior in mice, as proved by elevated plus maze and forced swim tests, respectively 22 . Therefore, we carried out an elevated plus maze test using 13A-, 13S- and 13L-CMs.…”

“…Among the RAN proteins that are generated from polyQ disease-causative genes, polyC peptide with 13 cysteine repeat was difficult to synthesize 22 , whereas, polyA, polyS, polyL having 13 repeats of the corresponding amino acids (13A, 13S and 13L) could be obtained and aggregated 22 , 24 . Thus, we sought to study toxicity of microglia having either of the three RAN peptides inside.…”

“…Similarly, polyA-, polyS-, polyL- and polyC-containing proteins were detected in the brain from patients with HD 21 . The RAN proteins are likely toxic to the brain because injection of polyS and polyL aggregates into the lateral ventricle led to altered brain functions in mice 22 .…”