|M.Sc Student||Bishara Sleman|
|Subject||Regulation of PINK1 in Parkinson's Disease|
|Department||Department of Medicine||Supervisor||Professor Simone Engelender|
|Full Thesis text|
Parkinson's disease PD is the second common neurodegenerative disease worldwide after Alzheimer’s disease. Its prevalence increases with age, rising to 1% in people aged more than 65 years. The clinical manifestation of PD can be divided into two major features: (i) motor symptoms (called ‘parkinsonism’), which include resting tremor, rigidity, bradykinesia (slowness in executing movement) and postural instability; and (ii) non-motor symptoms (e.g. cognitive dysfunction, autonomic nervous system dysfunction, sleep disorders). Pathological features include loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic protein inclusions termed Lewy bodies in surviving neurons.
PTEN- induced kinase1 (PINK1) gene contains 8 exons and encodes a 581 amino acid protein. The gene is ubiquitously transcripted and is predicted to encode an N-terminal 34 amino acid mitochondrial targeting sequence (MTS), a transmembrane domain (TMD) (residues 94-110) and a highly conserved protein kinase domain (residues 156-509).
Mutations in PINK1 kinase domain, has been reported to cause PD, which highlight the importance of PINK1 kinase activity in PD. Furthermore, mutations in PINK1 C-terminus region which regulates its kinase activity also cause PD. Collectively this data indicate that PINK1 kinase domain had a pivotal role in the pathogenesis of PD and loss of PINK1 kinase activity may induce PD.
While protease or lysosomal inhibition does not lead to PINK1 accumulation, inhibition of proteasome activity by the proteasome inhibitor lactacystin leads to PINK1 accumulation. Moreover, polyubiquitylated PINK1 is detected in the presence of proteasomal inhibitors. These results indicate that PINK1 degradation depends on the ubiquitin-proteasome system (UPS).
We investigated in this thesis the proteasomal degradation of PINK1, including the role of different E3 ubiquitin-ligases and clearance of PINK1. We believe that our data will shed light on how PINK1 levels are regulated in normal and pathological states, including PD.