Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein
Accumulation of α-Synuclein (αSyn) in nigral dopaminergic neurons is commonly seen in patients with Parkinson′s disease (PD). We recently reported that transduction of intracellular single-chain intrabody targeting the 53–87 amino acid residues of human αSyn by recombinant adeno associated viral vec...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
|
| Series: | Genes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4425/12/6/948 |
| _version_ | 1797529347328835584 |
|---|---|
| author | Yun-Hsiang Chen Kuo-Jen Wu Wei Hsieh Brandon K. Harvey Barry J. Hoffer Yun Wang Seong-Jin Yu |
| author_facet | Yun-Hsiang Chen Kuo-Jen Wu Wei Hsieh Brandon K. Harvey Barry J. Hoffer Yun Wang Seong-Jin Yu |
| author_sort | Yun-Hsiang Chen |
| collection | DOAJ |
| description | Accumulation of α-Synuclein (αSyn) in nigral dopaminergic neurons is commonly seen in patients with Parkinson′s disease (PD). We recently reported that transduction of intracellular single-chain intrabody targeting the 53–87 amino acid residues of human αSyn by recombinant adeno associated viral vector (AAV-NAC32) downregulated αSyn protein in SH-SY5Y cells and rat brain. This study characterizes the behavioral phenotype and dopaminergic protection in animals receiving AAV-NAC32. Our results show that adult DAT-Cre rats selectively overexpress αSyn in nigra dopaminergic neurons after local administration of AAV-DIO-αSyn. These animals develop PD-like phenotype, including bradykinesia and loss of tyrosine hydroxylase (TH) immunoreactivity in substantia nigra pars compacta dorsal tier (SNcd). An injection of AAV-NAC32 to nigra produces a selective antibody against αSyn and normalizes the behavior. AAV-NAC32 significantly increases TH, while reduces αSyn immunoreactivity in SNcd. Altogether, our data suggest that an AAV-mediated gene transfer of NAC32 antibody effectively antagonizes αSyn-mediated dopaminergic degeneration in nigra, which may be a promising therapeutic candidate for synucleinopathy or PD. |
| first_indexed | 2024-03-10T10:12:33Z |
| format | Article |
| id | doaj.art-428e5b98712d431caa279b5c368715c0 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T10:12:33Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-428e5b98712d431caa279b5c368715c02023-11-22T01:02:30ZengMDPI AGGenes2073-44252021-06-0112694810.3390/genes12060948Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha SynucleinYun-Hsiang Chen0Kuo-Jen Wu1Wei Hsieh2Brandon K. Harvey3Barry J. Hoffer4Yun Wang5Seong-Jin Yu6Department of Life Science, Fu-Jen Catholic University, New Taipei City 24205, TaiwanCenter for Neuropsychiatric Research, National Health Research Institutes, Zhunan 35053, TaiwanCenter for Neuropsychiatric Research, National Health Research Institutes, Zhunan 35053, TaiwanNational Institute on Drug Abuse IRP, NIH, Baltimore, MD 21224, USADepartment of Neurosurgery, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USACenter for Neuropsychiatric Research, National Health Research Institutes, Zhunan 35053, TaiwanCenter for Neuropsychiatric Research, National Health Research Institutes, Zhunan 35053, TaiwanAccumulation of α-Synuclein (αSyn) in nigral dopaminergic neurons is commonly seen in patients with Parkinson′s disease (PD). We recently reported that transduction of intracellular single-chain intrabody targeting the 53–87 amino acid residues of human αSyn by recombinant adeno associated viral vector (AAV-NAC32) downregulated αSyn protein in SH-SY5Y cells and rat brain. This study characterizes the behavioral phenotype and dopaminergic protection in animals receiving AAV-NAC32. Our results show that adult DAT-Cre rats selectively overexpress αSyn in nigra dopaminergic neurons after local administration of AAV-DIO-αSyn. These animals develop PD-like phenotype, including bradykinesia and loss of tyrosine hydroxylase (TH) immunoreactivity in substantia nigra pars compacta dorsal tier (SNcd). An injection of AAV-NAC32 to nigra produces a selective antibody against αSyn and normalizes the behavior. AAV-NAC32 significantly increases TH, while reduces αSyn immunoreactivity in SNcd. Altogether, our data suggest that an AAV-mediated gene transfer of NAC32 antibody effectively antagonizes αSyn-mediated dopaminergic degeneration in nigra, which may be a promising therapeutic candidate for synucleinopathy or PD.https://www.mdpi.com/2073-4425/12/6/948AAVsynucleinParkinson’s diseaseimmunotherapy |
| spellingShingle | Yun-Hsiang Chen Kuo-Jen Wu Wei Hsieh Brandon K. Harvey Barry J. Hoffer Yun Wang Seong-Jin Yu Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein Genes AAV synuclein Parkinson’s disease immunotherapy |
| title | Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein |
| title_full | Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein |
| title_fullStr | Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein |
| title_full_unstemmed | Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein |
| title_short | Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein |
| title_sort | administration of aav alpha synuclein nac antibody improves locomotor behavior in rats overexpressing alpha synuclein |
| topic | AAV synuclein Parkinson’s disease immunotherapy |
| url | https://www.mdpi.com/2073-4425/12/6/948 |
| work_keys_str_mv | AT yunhsiangchen administrationofaavalphasynucleinnacantibodyimproveslocomotorbehaviorinratsoverexpressingalphasynuclein AT kuojenwu administrationofaavalphasynucleinnacantibodyimproveslocomotorbehaviorinratsoverexpressingalphasynuclein AT weihsieh administrationofaavalphasynucleinnacantibodyimproveslocomotorbehaviorinratsoverexpressingalphasynuclein AT brandonkharvey administrationofaavalphasynucleinnacantibodyimproveslocomotorbehaviorinratsoverexpressingalphasynuclein AT barryjhoffer administrationofaavalphasynucleinnacantibodyimproveslocomotorbehaviorinratsoverexpressingalphasynuclein AT yunwang administrationofaavalphasynucleinnacantibodyimproveslocomotorbehaviorinratsoverexpressingalphasynuclein AT seongjinyu administrationofaavalphasynucleinnacantibodyimproveslocomotorbehaviorinratsoverexpressingalphasynuclein |