Protein-based inheritance is known to occur in yeast, where prions can adopt self-replicating structures. Recently, proteins containing intrinsically disordered regions (IDRs), or regions that lack a well-defined three- dimensional structure, were also shown to mediate inheritance in yeast (Chakrabortee et al. 2016). It is unknown whether prions or IDR proteins can mediate inheritance in animals. While studying the role of IDR proteins in dsRNA-mediated gene silencing (RNAi) in C. elegans, we made the following unexpected observation. In particular genetic backgrounds, the C. elegans IDR protein PGL-1 forms aggregate-like structures in germ cells. Amazingly, these PGL-1 aggregates are maintained in the germline (inherited) by animals for multiple generations after these animals no longer possess the mutation that originally triggered their formation. These data have led us to hypothesize that IDR proteins can form self-propagating aggregates in animals and thereby mediate transgenerational inheritance. This proposal uses C. elegans as an animal model system to test this central hypothesis, as well as explore, more generally, the incidence and consequence of heritable protein structures that occur in animal germlines. Interestingly, many IDR proteins form aggregates in the context of human disease. IDR protein aggregates are associated with proteinopathic diseases such as Alzheimer's, ALS, and Parkinson's disease. The pathological consequences of protein aggregation are widely believed to be limited to a single generation: Known protein aggregates form in aging somatic tissues, and the soma is not passed to progeny. This seeming constraint might be overcome, however, if a self-propagating protein aggregate were to form in the germline. Every animal (and every animal cell) alive today is directly related to germ cells that existed many millions of years ago. Thus, if self-propagating protein aggregates were to form in a germ cell, those aggregates might be passed from generation to generation, leading to long-term deleterious and heritable consequences. Therefore, we speculate that protein-based inheritance might explain some of the heritability of proteinopathies that remains unaccounted for to date. Our long-term goals are to determine the extent to which protein-based structures mediate inheritance in animals, and, ultimately, ask if and how structure-based inheritance contributes to the inheritance of disease in humans. This proposal is innovative because it describes the first example (that I am aware of) of a heritable protein aggregate (protein-based inheritance) in animals. This proposal is significant because it will likely advance our understanding of two important, yet poorly understood, areas of biology: protein aggregation and non-Mendelian transgenerational inheritance. Finally, the proposal is significant because the work we are doing may impact our understanding of the etiology and possibly the treatment of diseases such as human proteinopathic disorders.

Public Health Relevance

Proteins can contribute to diseases like Alzheimer's, ALS, and Huntington's when they adopt self-propagating pathological structures that convert newly translated proteins into the pathological state (termed proteinopahtic disease). The underlying causes for most cases of proteinopathic diseases in humans are not known. We are exploring the idea that protein aggregates, which are inherited via the germline, may contribute to these idiopathic proteinopathic diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Membrane Biology and Protein Processing Study Section (MBPP)
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Guo, Max
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Harvard Medical School
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