TY - JOUR
T1 - Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration
AU - Rana, Anil
AU - Seinen, Erwin
AU - Siudeja, Katarzyna
AU - Muntendam, Remco
AU - Srinivasan, Balaji
AU - Van Der Want, Johannes J.
AU - Hayflick, Susan
AU - Reijngoud, Dirk Jan
AU - Kayser, Oliver
AU - Sibon, Ody C.M.
PY - 2010/4/13
Y1 - 2010/4/13
N2 - Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN.
AB - Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN.
KW - Coenzyme A
KW - Lifespan
KW - Mitochondria
KW - Oxidative stress
KW - PKAN
UR - http://www.scopus.com/inward/record.url?scp=77951055908&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951055908&partnerID=8YFLogxK
U2 - 10.1073/pnas.0912105107
DO - 10.1073/pnas.0912105107
M3 - Article
C2 - 20351285
AN - SCOPUS:77951055908
SN - 0027-8424
VL - 107
SP - 6988
EP - 6993
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 15
ER -