UNDERSTANDING HOW THE PROTEIN QUALITY CONTROL MAINTAINS PROTEIN HOMEOSTASIS AND HOW ITS FAILURE LEADS TO AGING AND AGE-RELATED NEURODEGENERATIVE DISEASES
Maintaining protein homeostasis is crucial for cellular and organismal health. However, many errors can occur during DNA replication, transcription and translation that will lead to the production of polypeptides that are either mutated or truncated and that cannot acquire their native folding state.
The main source of misfolded proteins in mammalian cells are newly synthesized polypeptides that have not yet reached their native state and defective ribosomal products (DRiPs), which result from the misincorporation of amino acids, premature translation termination, damaged mRNAs or DNA mutations. DRiPs also include small translation products that are generated outside of protein-coding regions by so called pervasive translation. Regardless of their origin, once DRiPs and mutated/misfolded proteins are synthesized, they are recognized by specific protein quality control machineries. These include the molecular chaperones (e.g. HSP70s, HSP40s, small HSPs/HSPBs, BAG co-chaperones, VCP) and the degradative systems proteasome and autophagy. Failure to correctly handle misfolding-prone proteins can lead to the formation of cytotoxic aggregates, whose accumulation is a typical hallmark of many age-related neurodegenerative diseases.
Recent evidence is emerging for a strong link between phase-separating proteins, membraneless organelles, protein quality control failure and age-related diseases. Our recent data highlight an intricate connection between compartment dynamics and protein misfolding, including DRiP mishandling and lend support to the idea that aberrant changes in the dynamics of membrane-less organelles can drive cell dysfunction and disease (Ganassi et al., Mol Cell 2016; Morelli et al., Cell reports 2017; Alberti & Carra, JMB 2018).
The main focus of my research is to further understand the role of molecular chaperones in regulating the properties and functions of membraneless organelles, thus enabling dynamic cellular compartmentalization in response to physiological and external stimuli on the one hand and preventing age-related neurodegenerative and neuromuscular diseases, on the other hand. Finally, mutations in genes encoding for several HSPBs and the co-chaperone BAG3 leads to neurodegenerative and muscular diseases. We are also interested in understanding how these mutations cause disease and to what extent pathogenesis is linked to PQC failure.
