title: BPOZ-2 Gene Delivery Ameliorates Alpha-Synucleinopathy in A53T Transgenic Mouse Model of Parkinson's Disease.
abstract: Ankyrin-rich BTB/POZ domain containing protein-2 or BPOZ-2, a scaffold protein, has been recently shown to control the degradation of many biological proteins ranging from embryonic development to tumor progression. However, its role in the process of neuronal diseases has not been properly explored. Since, abnormal clearance of metabolic proteins contributes to the development of alpha-synuclein (α-syn) pathologies in Parkinson's disease (PD), we are interested to explore if BPOZ-2 participates in the amelioration of α-syn in vivo in basal ganglia. Here we report that lentiviral administration of bpoz-2 gene indeed lowers the burden of α-syn in DA neurons in the nigra of A53T transgenic (A53T-Tg) mouse. Our detailed immunological analyses have shown that the overexpression of bpoz-2 dramatically improves both somatic and neuritic α-syn pathologies in the nigral DA neurons. Similarly, the specific ablation of bpoz-2 by lentiviral-shRNA stimulates the load of monomeric and polymeric forms of α-syn in the nigral DA neurons of A53T-Tg. While investigating the mechanism, we observed that BPOZ-2 was involved in a protein-protein association with PINK1 and therefore could stimulate PINK1-dependent autophagic clearance of α-syn. Our results have demonstrated that bpoz-2 gene delivery could have prospect in the amelioration of alpha-synucleinopathy in PD and other Lewy body diseases.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Avik
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Suresh Babu
authors.initials: SB
authors.lastname: Rangasamy
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Madhuchhanda
authors.initials: M
authors.lastname: Kundu
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.|Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, 820 South Darnen Avenue, Chicago, IL, USA.
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029742:Caenorhabditis elegans Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D051844:alpha-Synuclein; C585874:Abtb2 protein, mouse; C000592695:pink-1 protein, C elegans; D000099202:PTEN-Induced Putative Kinase