|M.Sc Student||Abu-Alhiga Fatimah|
|Subject||Regulation of PINK1 homeostasis in Parkinson's disease|
|Department||Department of Medicine||Supervisor||Professor Simone Engelender|
|Full Thesis text|
Parkinson's disease (PD) is a common neurodegenerative disorder. It is a
progressively disabling neurodegenerative disorder that occurs late in life, causing motor symptoms, such as rigidity, bradykinesia and tremors. In addition, more recently, different non-motor symptoms, such as autonomic dysfunction, sleep disorders and cognitive dysfunction have been associated to PD as well. At the pathological level, there is characteristic loss of dopaminergic neurons in the substantia-nigra pars compacta (SNpc) and the presence of cytoplasmic protein inclusions termed Lewy bodies in surviving neurons.
PTEN-induced kinase1 (PINK1) is involved in autosomal recessive and early-onset PD. It is a serine-threonine kinase that is localized at the mitochondria. PINK1 protects cells against several toxic insults, which is abrogated by disease-mutations, suggesting that dysfunction of PINK1 might play a role in the pathogenesis of PD. In agreement, knockout of PINK1 in Drosophila results in mitochondrial dysfunction and in the death of dopaminergic neurons.
Pharmacological inhibition of proteasome activity was shown to lead to PINK1 accumulation. Indicating that PINK1 degradation depends on the ubiquitin-proteasome system (UPS). SIAH protein is an E3 ubiquitin-ligase that is involved in ubiquitination and proteasome-mediated degradation of specific proteins. A compromised proteasome activity in PD may lead to the accumulation of damaged or misfolded protein in the disease. Such protein accumulation may contribute to the pathogenesis of PD.
We have previously shown in our laboratory that SIAH ubiquitinates different PD Proteins, including synphilin-1 and α-synuclein, suggesting that SIAH-1 may play a role in PD. We now obtained results showing that SIAH-1 interacts with and ubiquitinates PINK1.The ubiquitination promoted by SIAH-1 leads to the proteasomal degradation of PINK1. We also investigated the interaction of SIAH-1 with PINK1 disease-mutants and its ability to promote their ubiquitination and degradation. We found that a frequent PINK1 mutation, G309D, is less degraded by SIAH-1, supporting the importance and specificity of PINK1ubiquitination and degradation by SIAH-1. Moreover, we investigated the role of SIAH-3 in the ability of SIAH-1 to ubiquitinate PINK1. We found that SIAH-3 negatively regulates SIAH-1 ubiquitin-ligase activity, decreasing the ubiquitination of PINK1 and promoting its cellular accumulation, independent of the polarization status of the mitochondria.
We raise the possibility that the ubiquitination of PINK1 by SIAH-1 is an important event in the cell, responsible to control PINK1 availability to maintain mitochondrial homeostasis. In addition, dysfunction of PINK1-SIAH-1 interaction and ubiquitination occur in the presence of PINK1 mutations and SIAH-3, with implications for the mitochondrial dysfunction observed in the disease.