Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s Disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are the group of disorders characterized by progressive degeneration of the structure and function of the nervous system. These all diseases primarily affect neurons, leading to their dysfunction and eventual death. To control the death rate, the ubiquitin-proteasome system maintains protein homeostasis in neurons and controls protein stability. Synapse remodeling is the synaptic plasticity. It is a junction between two nerve cells or between a neuron and another type of cell (such as a muscle cell or gland cell) that allows them to communicate. This process is required for brain development, learning, memory, adaptive behavior, and environmental change. The UPS regulates this process by modulating the levels of synaptic proteins, thereby influencing the structure and function of synapses. The ubiquitin-proteasome system is integral to synaptic function and plasticity, and its dysfunction is a common feature in neurodegenerative diseases. Continued research into the precise mechanisms and regulation of the UPS in neurons holds promise for developing targeted therapies for these debilitating conditions. The ubiquitin-proteasome system is integral to synaptic function and plasticity, and its dysfunction is a common feature in neurodegenerative diseases. Continued research into the precise mechanisms and regulation of the UPS in neurons holds promise for developing targeted therapies for these debilitating conditions. In this chapter, we will discuss a comprehensive review of the ubiquitin-proteasome system in synapse remodeling and neurodegenerative diseases.