title: Cerebellar abnormalities in purine nucleoside phosphorylase deficient mice.
abstract: Inherited defects in purine nucleoside phosphorylase (PNP) cause severe T cell immunodeficiency and progressive neurological dysfunction, yet little is known about the effects of PNP deficiency on the brain. PNP-KO mice display metabolic and immune anomalies similar to those observed in patients. Our objectives were to characterize brain abnormalities in PNP-KO mice and determine whether restoring PNP activity prevents these abnormalities. We analyzed structural brain defects in PNP-KO mice by magnetic resonance imaging, while assessing motor deficits using the accelerating rotarod and stationary balance beam tests. We detected morphological abnormalities and apoptosis in the cerebellum of PNP-KO mice by hematoxylin and eosin, electron microscopy, TUNEL and activated caspase 3 staining. We treated PNP-KO mice with PNP fused to the HIV-TAT protein transduction domain (TAT-PNP) from birth or from 4 weeks of age. Magnetic resonance imaging revealed a smaller than normal cerebellum in PNP-KO mice. PNP-KO mice displayed motor abnormalities including rapid fall from the rotating rod and frequent slips from the balance beam. The cerebellum of PNP-KO mice contained reduced purkinje cells (PC), which were irregular in shape and had degenerated dendrites. PC from the cerebellum of PNP-KO mice, expanded ex vivo, demonstrated increased apoptosis, which could be corrected by supplementing cultures with TAT-PNP. TAT-PNP injections restored PNP activity in the cerebellum of PNP-KO mice. TAT-PNP from birth, but not treatment initiated at 4 weeks of age, prevented the cerebellar PC damage and motor deficits. We conclude that PNP deficiency cause cerebellar abnormalities, including PC damage and progressive motor deficits. TAT-PNP treatment from birth can prevent the neurological abnormalities in PNP-KO mice.
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Alireza
authors.initials: A
authors.lastname: Mansouri
authors.forename: Weixian
authors.initials: W
authors.lastname: Min
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Cole
authors.forename: Sheena A
authors.initials: SA
authors.lastname: Josselyn
authors.forename: Jeffrey Theodore
authors.initials: JT
authors.lastname: Henderson
authors.forename: Matthijs
authors.initials: M
authors.lastname: van Eede
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Cameron
authors.initials: C
authors.lastname: Ackerley
authors.forename: Eyal
authors.initials: E
authors.lastname: Grunebaum
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
mesh_terms: D000818:Animals; D002526:Cerebellar Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D002531:Cerebellum / Q000002:abnormalities / Q000201:enzymology / Q000473:pathology; D018450:Disease Progression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000201:enzymology / Q000473:pathology
chemical_list: D011683:Purine-Nucleoside Phosphorylase