TY - JOUR
T1 - Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress
AU - Muqit, Miratul M. K.
AU - Abou-Sleiman, Patrick M.
AU - Saurin, Adrian T.
AU - Harvey, Kirsten
AU - Gandhi, Sonia
AU - Deas, Emma
AU - Eaton, Simon
AU - Payne Smith, Martin D.
AU - Venner, Kerrie
AU - Matilla, Antoni
AU - Healy, Daniel G.
AU - Gilks, William P.
AU - Lees, Andrew J.
AU - Holton, Janice
AU - Revesz, Tamas
AU - Parker, Peter J.
AU - Harvey, Robert J.
AU - Wood, Nicholas W.
AU - Latchman, David S.
PY - 2006/7
Y1 - 2006/7
N2 - Following our identification of PTEN-induced putative kinase 1 (PINK1) gene mutations in PARK6-linked Parkinson's disease (PD), we have recently reported that PINK1 protein localizes to Lewy bodies (LBs) in PD brains. We have used a cellular model system of LBs, namely induction of aggresomes, to determine how a mitochondrial protein, such as PINK1, can localize to aggregates. Using specific polyclonal antibodies, we firstly demonstrated that human PINK1 was cleaved and localized to mitochondria. We demonstrated that, on proteasome inhibition with MG-132, PINK1 and other mitochondrial proteins localized to aggresomes. Ultrastructural studies revealed that the mechanism was linked to the recruitment of intact mitochondria to the aggresome. Fractionation studies of lysates showed that PINK1 cleavage was enhanced by proteasomal stress in vitro and correlated with increased expression of the processed PINK1 protein in PD brain. These observations provide valuable insights into the mechanisms of LB formation in PD that should lead to a better understanding of PD pathogenesis.
AB - Following our identification of PTEN-induced putative kinase 1 (PINK1) gene mutations in PARK6-linked Parkinson's disease (PD), we have recently reported that PINK1 protein localizes to Lewy bodies (LBs) in PD brains. We have used a cellular model system of LBs, namely induction of aggresomes, to determine how a mitochondrial protein, such as PINK1, can localize to aggregates. Using specific polyclonal antibodies, we firstly demonstrated that human PINK1 was cleaved and localized to mitochondria. We demonstrated that, on proteasome inhibition with MG-132, PINK1 and other mitochondrial proteins localized to aggresomes. Ultrastructural studies revealed that the mechanism was linked to the recruitment of intact mitochondria to the aggresome. Fractionation studies of lysates showed that PINK1 cleavage was enhanced by proteasomal stress in vitro and correlated with increased expression of the processed PINK1 protein in PD brain. These observations provide valuable insights into the mechanisms of LB formation in PD that should lead to a better understanding of PD pathogenesis.
KW - Autosomal-recessive juvenile parkinsonism
KW - Lewy body
KW - Microtubule organizing centre
KW - Mitochondrial processing peptidase
KW - Parkinson's disease
KW - Ubiquitin-proteasome system
UR - http://www.scopus.com/inward/record.url?scp=33745068109&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2006.03845.x
DO - 10.1111/j.1471-4159.2006.03845.x
M3 - Article
C2 - 16805805
AN - SCOPUS:33745068109
SN - 0022-3042
VL - 98
SP - 156
EP - 169
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 1
ER -
