Koyuncu, S. | bioRxiv Science

bioRxiv2023

Neuroprotective effects of hepatoma-derived growth factor in models of Huntington's disease

Huntingtons disease (HD) is a movement disorder caused by a mutation in the Huntingtin gene, that leads to severe neurodegeneration and inevitable death of the patients. Molecular mechanisms of HD are still not sufficiently understood, and no cure is currently available. Here, we demonstrate neuroprotective effects of hepatoma-derived growth factor (HDGF) in cellular and mouse models of HD. We show that HDGF expression levels in neuronal cell types inversely correlate with cellular vulnerability to HD. Moreover, lack of endogenous HDGF shortened lifespan and worsened rotarod performance of R6/2 HD model mice. AAV-mediated delivery of HDGF into the brain reduced mutant Huntingtin inclusion body load, but had no significant effect on motor behavior or lifespan. Interestingly, both nuclear and cytoplasmic versions of HDGF were equally efficient in rescuing mutant Huntingtin toxicity in cell culture models of HD. Moreover, extracellular application of a recombinant HDGF protein improved viability of mutant Huntingtin-expressing primary neurons and reduced mutant Huntingtin aggregation in neural progenitor cells differentiated from human patient-derived induced pluripotent stem cells (iPSCs). Our findings provide new insights into the pathomechanisms of HD and suggest neuroprotective potential of HDGF in neurodegeneration.

neuroscience↗

bioRxiv2022

Chloroplast protein import determines plant proteostasis and retrograde signaling

Proteins containing polyglutamine (polyQ) repeats are prone to aggregation and can lead to distinct human pathologies. For instance, Huntingtons disease is caused by an abnormal expansion of the polyQ stretch (> Q35) of Huntingtin (HTT) protein. However, plants express hundreds of proteins containing polyQ regions, but no pathologies arising from these factors have been reported to date. Here, we ask how plants maintain the proteostasis of polyQ-containing proteins, which are intrinsically enriched in the plant proteomes. To this end, we overexpressed an aggregation-prone fragment of human HTT (Q69) in plant cells. In contrast to invertebrate and mammalian transgenic models, we find that Arabidopsis thaliana plants suppress Q69 aggregation. This elevated proteostasis ability is mediated through the import and degradation of Q69 in chloroplasts. Conversely, inhibition of chloroplast protein import either genetically or pharmacologically reduces the capacity of plant cells to prevent Q69 aggregation. We find that Q69 interacts with the chloroplast stromal processing peptidase (SPP). Notably, expression of synthetic Arabidopsis SPP is sufficient to suppress aggregation of polyQ-expanded HTT in human cells. Beyond ectopically expressed Q69-HTT, endogenous polyQ-containing proteins also aggregate in Arabidopsis upon inhibition of chloroplast import. Among them, the plastid casein kinase 2 (pCK2), which contains a polyQ region next to the chloroplast targeting sequence motif, can also be localized into the nucleus. Upon inhibition of chloroplast import, pCK2 accumulates at higher levels in the nucleus and forms diamond-shaped amyloid-like fibrils surrounding the chloroplasts. These results indicate that the differential conformation and redistribution of pCK2 to the nucleus depends on chloroplast import efficiency, providing a role of polyQ repeats in chloroplast to nucleus communication (i.e. retrograde signaling). Together, our findings establish chloroplast protein import and proteases as determinants of polyQ proteostasis, with important implications for plant biology that can also lead to therapeutic approaches for human diseases that involve protein aggregation.

plant biology↗