|Ph.D Student||Dabool Lital|
|Subject||Characterizing Molecular Mechanisms|
of Neurodegeneration using the Drosophila
|Department||Department of Medicine||Supervisors||Professor Adi Salzberg|
|Dr. Estee Kurant|
|Full Thesis text|
Neurodegenerative diseases result from progressive neuronal loss and synaptic abnormalities within the central nervous system (CNS), eventually leading to dysfunction of motor and cognitive abilities. One prominent feature of neurodegeneration is the formation of specific protein aggregates either intra or extracellularly. Parkinson's disease (PD) is the second most common degenerative brain disorder, which is characterized by the specific degeneration of dopaminergic (DA) neurons and intraneuronal aggregates named Lewy bodies. The major component of these protein aggregates is the human protein α-Synuclein (α-Syn).
Drosophila melanogaster flies constitute an important model organism to study neurodegeneration as they carry many orthologue genes and conserved cellular pathways with mammals, including those involved in neuronal development and function. In this work, we present an adult fly model of PD, which enables the study of genes essential for development in neurodegeneration. This model directs the specific expression of the human protein α-Syn, to the adult brain of the fly.
Former studies have indicated an important gene associated with PD named skp1. It encodes a component of E3 ubiquitin ligase, which interacts with several F-box proteins, each of them is responsible for targeting specific proteins for degradation. Here we show that its Drosophila homologue, skpA, plays an important role in the adult fly brain since its specific neuronal knockdown leads to formation of ubiquitinated protein aggregates and loss of DA neurons. Moreover, we discovered that skpA overexpression specifically in adult neurons improves motor abilities and prolongs life span of wild type flies and importantly, significantly rescues neurodegeneration in the adult Drosophila PD model.
Our data demonstrate that an F-box protein named Nutcracker (NTc) functions downstream of SkpA in the same pathway in the adult fly brain. However, in the absence of NTc, SkpA is capable of interacting with alternative F-box proteins in the adult CNS.
In conclusion, this work provides evidence for the substantial role of skpA in neurodegeneration and highlights its validity as a diagnostic marker and as a gene therapy or pharmacological agent target to focus on in future neurodegeneration studies.