title: Heat Shock Protein Beta-1 Modifies Anterior to Posterior Purkinje Cell Vulnerability in a Mouse Model of Niemann-Pick Type C Disease.
abstract: Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC) disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1), promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Chan
authors.identifier: 0000-0003-0510-8996
authors.initials: C
authors.lastname: Chung
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Matthew J
authors.identifier: 0000-0001-8565-7535
authors.initials: MJ
authors.lastname: Elrick
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Dell'Orco
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Zhaohui S
authors.initials: ZS
authors.lastname: Qin
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Shanker
authors.initials: S
authors.lastname: Kalyana-Sundaram
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Vikram G
authors.initials: VG
authors.lastname: Shakkottai
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use
chemical_list: D055551:HSP27 Heat-Shock Proteins; D034741:RNA, Small Interfering