To ensure proper functionality, cells have evolved sophisticated mechanisms to maintain the homeostasis of the protein pool in term of conformation, stability, abundance and cellular localization. Alterations in protein homeostasis and conformation are the molecular hallmark of misfolding diseases, including the neurodegenerative disorders, i.e., Alzheimer’s, Parkinson’s. Our research is focused on understanding the principles governing the protein biogenesis and how these processes are related to normal physiology and diseases using biophysical, biochemical, cell biological and systems biology approaches. A central theme is to decipher the mechanisms by which environmental factors, i.e., aging and stress, or pathogenic mutations, including silent polymorphisms, affect the molecular properties of the proteins and their folding fidelity and induce the disease state. Ongoing projects in our laboratory are dedicated to elucidate the mechanisms of protein misfolding in the polyglutaine neurodegenerative disorders, i.e., Huntington’s disease and several spinocereberellar ataxia. We seek also to understand the impact of the osmoregulatory substances involved in cell volume homeostasis on the pathology of the polyglutamine disease with the aim to design a therapeutic platform to ameliorate neurodegenerative phenotype.