Metalloregulation of Protein Clearance: New Therapeutic Avenues for Neurodegenerative Diseases

Abstract Metals are critical for several brain functions, mainly because they participate in pathways that govern neurotransmission, protein expression, and protein clearance. Copper, iron, and zinc are concentrated in protein aggregates associated with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. These observations have focused most research effort on the pathological role of these metals in β-amyloid and α-synuclein aggregation. However, there is evidence that physiological levels of copper, iron, and zinc regulate protein degradative pathways that are important for the clearance of misfolded protein aggregates. This review summarizes how transition metals can regulate cellular protein degradation, with emphasis on the ubiquitin proteasome system and lysosome-autophagy pathway. This information can be useful to design new therapeutic treatments to increase the clearance of the toxic proteins associated with these devastating diseases.