Parkinson's disease (PD) is associated with intracellular aggregation of alpha-synuclein (aSyn). However, the molecular mechanism of aSyn aggregation is not well understood. Our hypothesis is that alteration of essential interactions of aSyn during its translation (when it is still in the process of synthesis) leads to its misfolding and aggregation triggering initiation of the disease process. These changes of interactions can be triggered by a mutation (familial PD) or by defects in binding factors (sporadic PD). This hypothesis is supported by our experimental studies conducted on several proteins associated with human diseases: granulin (frontotemporal dementia), CFTR (cystic fibrosis), prolactin (infertility), and also by the recent discovery of a novel pathway of translational regulation, RAPP, that sensors quality of nascent chains during translation.
Two specific aims are proposed to test this hypothesis:
Aim 1 : To identify aSyn interacting partners during translation in health and disease. We will use advantage of the recently developed unique approach iPINCH to identify the interacting proteins for wild-type and mutated (A30P, E46K, A53T) aSyns.
Aim 2 : Use a candidate approach to test involvement of folding, targeting and protein quality control factors in aSyn expression and folding. Recent studies demonstrate that ribosome-associated chaperones, chaperonins and components of RAPP pathway interact with nascent chains during translation. We will test their involvement in the expression and folding of wild-type and mutated aSyns by their RNAi knockdowns in cultured human cells. This project will lead to better understanding of the molecular mechanism of aSyn aggregation and identification of potential pharmacological targets for the disease treatments.
Parkinson's disease is associated with aggregation of alpha-synuclein (aSyn), but the mechanism of aggregation is not well understood. During translation proteins interact with ribosome-associated proteins, these interactions are important for protein folding, however little is known about these interactions for aSyn. We hypothesize that when aSyn loses these essential interactions, it misfolds and aggregates, and this project will test the hypothesis and identify co-translational aSyn interactions during its synthesis in health and disease.
|Pinarbasi, Emile S; Karamyshev, Andrey L; Tikhonova, Elena B et al. (2018) Pathogenic Signal Sequence Mutations in Progranulin Disrupt SRP Interactions Required for mRNA Stability. Cell Rep 23:2844-2851|
|Karamyshev, Andrey L; Karamysheva, Zemfira N (2018) Lost in Translation: Ribosome-Associated mRNA and Protein Quality Controls. Front Genet 9:431|