Dissecting neuronal regulatory pathways of the cellular heat shock response to elevated temperatures and misfolded proteins
Final Report Abstract
Proteinopathies are characterized by the chronic expression of misfolded proteins. The aggregation process was anticipated to take place strictly cell autonomously and unaffected by the cellular environment. Accumulating evidence now suggests, that cell‐to‐cell transmission of protein aggregates might occur in several neurodegenerative disorders and contribute to disease pathology. To test whether cytosolic protein aggregates can spread in a multicellular organism we used the yeast prion protein Sup35p, a cytosolic protein that is able to propagate its aggregated conformation in yeast and in mammalian cell culture. We generated transgenic Caenorhabditis elegans lines expressing the prion domain (NM) of Sup35p, as well as Sup35NM bearing a deletion in the oligorepeat region (RΔ2‐5) or an extended oligorepeat region (R2E2). Similarly as in yeast, these proteins aggregate in an oligorepeat region length dependent manner: R2E2 is highly aggregation‐prone, whereas RΔ2‐5 remains mostly soluble. Upon co‐expression in the same cells, R2E2 promotes the aggregation of RΔ2‐5, despite a very low or only transient co‐localization. Although expressed under a muscle cell specific promoter, R2E2 was detected in coelomocytes, phagocytes residing in the body cavity, indicating that R2E2 is being released from muscle cells. Remarkably, R2E2 was able to induce RΔ2‐5 aggregation expressed in another tissue. Thus, in a multicellular organism, compromised cells are able to affect global proteostasis in a non‐cell autonomous manner.
Publications
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Prion‐like
propagation
of
cytosolic
protein
aggregates:
insights
from
cell
culture
models.
Prion.
Oct.
2009
Krammer C, Schaetzl HM, Vorberg I
