Pathogenic effects of novel mutations in the P-Type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb Syndrome, a form of early-onset Parkinsonism

Jin-Sung Park, Prachi Mehta, Antony A. Cooper, David Veivers, Andre Heimbach, Barbara Stiller, Christian Kubisch, Victor S. Fung, Dimitri Krainc, Alan Mackay-Sim, Carolyn M. Sue

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS. Hum Mutat 32:956-964, 2011. (C) 2011 Wiley-Liss, Inc.

LanguageEnglish
Pages956-964
Number of pages9
JournalHuman mutation
Volume32
Issue number8
DOIs
Publication statusPublished - Aug 2011
Externally publishedYes

Keywords

  • Kufor-Rakeb syndrome
  • KRS
  • early-onset parkinsonism
  • ATP13A2
  • PARK9
  • proteasomal pathway
  • nonsense-mediated mRNA decay
  • ALPHA-SYNUCLEIN
  • JUVENILE PARKINSONISM
  • ENDOPLASMIC-RETICULUM
  • OLFACTORY MUCOSA
  • DISEASE
  • CELLS
  • STRESS
  • NEURODEGENERATION
  • AUTOPHAGOSOMES
  • LYSOSOMES

Cite this

Park, Jin-Sung ; Mehta, Prachi ; Cooper, Antony A. ; Veivers, David ; Heimbach, Andre ; Stiller, Barbara ; Kubisch, Christian ; Fung, Victor S. ; Krainc, Dimitri ; Mackay-Sim, Alan ; Sue, Carolyn M. / Pathogenic effects of novel mutations in the P-Type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb Syndrome, a form of early-onset Parkinsonism. In: Human mutation. 2011 ; Vol. 32, No. 8. pp. 956-964.
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title = "Pathogenic effects of novel mutations in the P-Type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb Syndrome, a form of early-onset Parkinsonism",
abstract = "Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS. Hum Mutat 32:956-964, 2011. (C) 2011 Wiley-Liss, Inc.",
keywords = "Kufor-Rakeb syndrome, KRS, early-onset parkinsonism, ATP13A2, PARK9, proteasomal pathway, nonsense-mediated mRNA decay, ALPHA-SYNUCLEIN, JUVENILE PARKINSONISM, ENDOPLASMIC-RETICULUM, OLFACTORY MUCOSA, DISEASE, CELLS, STRESS, NEURODEGENERATION, AUTOPHAGOSOMES, LYSOSOMES",
author = "Jin-Sung Park and Prachi Mehta and Cooper, {Antony A.} and David Veivers and Andre Heimbach and Barbara Stiller and Christian Kubisch and Fung, {Victor S.} and Dimitri Krainc and Alan Mackay-Sim and Sue, {Carolyn M.}",
year = "2011",
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doi = "10.1002/humu.21527",
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Park, J-S, Mehta, P, Cooper, AA, Veivers, D, Heimbach, A, Stiller, B, Kubisch, C, Fung, VS, Krainc, D, Mackay-Sim, A & Sue, CM 2011, 'Pathogenic effects of novel mutations in the P-Type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb Syndrome, a form of early-onset Parkinsonism', Human mutation, vol. 32, no. 8, pp. 956-964. https://doi.org/10.1002/humu.21527

Pathogenic effects of novel mutations in the P-Type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb Syndrome, a form of early-onset Parkinsonism. / Park, Jin-Sung; Mehta, Prachi; Cooper, Antony A.; Veivers, David; Heimbach, Andre; Stiller, Barbara; Kubisch, Christian; Fung, Victor S.; Krainc, Dimitri; Mackay-Sim, Alan; Sue, Carolyn M.

In: Human mutation, Vol. 32, No. 8, 08.2011, p. 956-964.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pathogenic effects of novel mutations in the P-Type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb Syndrome, a form of early-onset Parkinsonism

AU - Park, Jin-Sung

AU - Mehta, Prachi

AU - Cooper, Antony A.

AU - Veivers, David

AU - Heimbach, Andre

AU - Stiller, Barbara

AU - Kubisch, Christian

AU - Fung, Victor S.

AU - Krainc, Dimitri

AU - Mackay-Sim, Alan

AU - Sue, Carolyn M.

PY - 2011/8

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AB - Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS. Hum Mutat 32:956-964, 2011. (C) 2011 Wiley-Liss, Inc.

KW - Kufor-Rakeb syndrome

KW - KRS

KW - early-onset parkinsonism

KW - ATP13A2

KW - PARK9

KW - proteasomal pathway

KW - nonsense-mediated mRNA decay

KW - ALPHA-SYNUCLEIN

KW - JUVENILE PARKINSONISM

KW - ENDOPLASMIC-RETICULUM

KW - OLFACTORY MUCOSA

KW - DISEASE

KW - CELLS

KW - STRESS

KW - NEURODEGENERATION

KW - AUTOPHAGOSOMES

KW - LYSOSOMES

U2 - 10.1002/humu.21527

DO - 10.1002/humu.21527

M3 - Article

VL - 32

SP - 956

EP - 964

JO - Human mutation

T2 - Human mutation

JF - Human mutation

SN - 1059-7794

IS - 8

ER -