Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which affects 47 million patients worldwide. However, the underlying molecular mechanisms leading to sporadic-AD remain largely unknown and preventive treatment is not yet available. Lately, the ubiquitin-proteasome system as well as Golgi fragmentation were observed in neurodegenerative disorders and linked to AD. In this work we aimed to identify the regulatory mechanisms of E3 ligases that are involved in fragmentation of the Golgi apparatus in neurons. Specifically, our goal was to identify ubiquitin-dependent determinants that regulate Golgi homeostasis and integrity under the Golgi stress and characterize their involvement in AD. We intend to do so by three interconnected yet independent aims/objectives: (a) Identify ubiquitin E3 ligases that are involved in response to Golgi stress (b) Decipher the cellular role of putative Golgi-related E3s in AD using molecular, biochemical and cellular systems (c) Determine the effects of perturbation of Golgi-associated E3 ligases in vivo. Specifically, we identify critical determinants that regulate Golgi homeostasis and also can be affected under Golgi stress. We reveald the Zinc finger protein-like 1 (ZFPL1) as a crucial E3 ligase for Golgi homeostasis maintenance. Also, using state-of-the-art proteomic and glycomic approaches, we mapped the PTM landscape (Ub and glycosylation state) in cerebral spinal fluid (CSF) of different neuronal pathologies and revealed differential PTM patterns that are associated with different physiological states. Thus, our work highlights novel PTMs that are associated with AD and identified a novel E3 ligase that is involved in Golgi fragmentation in neurodegeneration and AD, which we will further examine to determine its role in controlling Golgi homeostasis and neurodegeneration.
