Neurodegenerative diseases are major health challenges in the aged population and profoundly affect the life expectancy and quality of life of the elderly people. These diseases are caused by a buildup of aggregation-prone proteins (e.g. Amyloid β (Aβ) and tau in Alzheimer’s disease, PolyQ proteins (Htt, Atx3n) in Huntington’s disease, α-synuclein in Parkinson’s disease, and TDP43 or SOD1 in Amyotrophic Lateral Sclerosis (ALS)). Build-up of these harmful proteins causes additional damages to the cells such as mitochondrial dysfunction, build-up of reactive oxygen species, and eventually causes cell death [1]. On the other hand, decreasing such aggregation-prone proteins has been shown to reverse neurodegeneration phenotypes, indicating the crucial importance of abnormal-protein build up as the crucial cause of neurodegenerative diseases. The build-up of these proteins are associated with a decline of protein degradation capacity of the cells, and consequently therapeutic strategies have been developed, and more are under development to enhance the clearance of these abnormal proteins by two major cellular protein degradation systems: the Ubiquitin-Proteasome System (UPS) [2] and the autophagylysosomal system [3]. In this editorial I would like to briefly review our current knowledge about the role of protein degradation systems in the development and therapy of neurodegenerative diseases. I will particularly focus on the cellular process of protein aggregation via key factors such as p97/VCP, p62, and HDAC6.