MPA-ND · Membrane protein aggregation and its links with neurodegenerative diseases

Membrane protein aggregation and its links with neurodegenerative diseases

Protein misfolding and aggregation have been linked with many fatal human disorders, including Alzheimer’s and Parkinson’s diseases. These disorders represent the fastest-growing cause of death in developed countries and are putting our healthcare system under severe stress. The amyloid hypothesis is regarded as one of the most promising causative theories of Alzheimer’s disease and is still being studied extensively. The hypothesis is based on the observation that patient brains contain protein plaques. The structure of these plaques has been studied in much detail; they primarily contain a part of the protein APP, which precursor is originally spanning the cell membrane. Within these plaques, APP has adopted a misfolded beta-sheet structure with fibrillar morphology, referred to as amyloid fibrils. In addition to the specific proteins directly associated with neurodegenerative diseases, widespread aggregation of numerous other proteins into amyloid fibrils has been observed and is likely to contribute to disease progression. In this context, recent studies have highlighted the key roles that membrane protein aggregation may play in misfolding diseases. In follow-up of this work, we set out two projects to increase our insights in the potential role of membrane proteins in neurodegeneration. * The propensity to misfold and self-assemble into stable aggregates is increasingly being recognized as a common feature of protein molecules. Studies thus far, however, have been almost exclusively focused on cytosolic proteins, resulting in a lack of detailed information about the misfolding and aggregation of membrane proteins. As a consequence, although such proteins make up approximately 30% of the human proteome and have high propensities to aggregate, relatively little is known about the biophysical nature of their assemblies. To shed light on this issue, a first goal of our study is to elucidate the structures of aggregates formed by model membrane proteins, such as E. coli lactose permease. * The high aggregation propensity of membrane proteins (Cyriam, Kundra et al 2015 Trends in Pharmacological Sciences) correlates with their downregulation in Alzheimer’s disease (AD), as established for a subset of proteins referred to as the ‘AD metastable subproteome’(Cyriam, Kundra et al 2016 PNAS). This metastable subproteome includes several pathways, most notably the oxidative phosphorylation which is enriched in mitochondrial membrane proteins. Many mitochondrial membrane proteins are encoded in the nucleus and are likely to pose risks to the cell upon their translation and import into the mitochondria. This finding suggests the presence of a specific link between protein aggregation, and mitochondrial dysfunction which has been identified as an early event in several neurodegenerative diseases, including AD. To investigate in detail the nature of this link, we set out to use different S. cerevisiae models of challenged mitochondrial import to investigate whether mitochondrial membrane proteins indeed aggregate under these conditions, how the cellular homeostasis network responds to such aggregation, and what are the structural features of the formed aggregates.

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