Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease
Abstract Background Parkinson’s disease (PD) is a neurodegenerative disease characterized by intraneuronal Lewy Body (LB) aggregates composed of misfolded alpha-synuclein (α-syn). The spread of misfolded α-syn follows a typical pattern: starting in the olfactory bulb (OB) and the gut, this pathology...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2018-09-01
|
Series: | Translational Neurodegeneration |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s40035-018-0128-6 |
id |
doaj-141e7e8caff14fc582aa8b4f6f6aaff0 |
---|---|
record_format |
Article |
spelling |
doaj-141e7e8caff14fc582aa8b4f6f6aaff02020-11-25T01:36:37ZengBMCTranslational Neurodegeneration2047-91582018-09-017111710.1186/s40035-018-0128-6Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s diseaseHaichen Niu0Lingyu Shen1Tongzhou Li2Chao Ren3Sheng Ding4Lei Wang5Zhonghai Zhang6Xiaoyu Liu7Qiang Zhang8Deqin Geng9Xiujuan Wu10Haiying Li11Department of Genetics, Xuzhou Medical UniversityDepartment of Epidemiology and Health Statistics, Xuzhou Medical UniversityDepartment of Epidemiology and Health Statistics, Xuzhou Medical UniversityDepartment of Neurology, Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityDepartment of Epidemiology and Health Statistics, Xuzhou Medical UniversityDepartment of Genetics, Xuzhou Medical UniversityDepartment of Genetics, Xuzhou Medical UniversityCollege of Medicine, Institute for Behavioral Medicine Research, The Ohio State UniversityDepartment of Genetics, Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Epidemiology and Health Statistics, Xuzhou Medical UniversityDepartment of Pathology, Xuzhou Medical UniversityAbstract Background Parkinson’s disease (PD) is a neurodegenerative disease characterized by intraneuronal Lewy Body (LB) aggregates composed of misfolded alpha-synuclein (α-syn). The spread of misfolded α-syn follows a typical pattern: starting in the olfactory bulb (OB) and the gut, this pathology is followed by the progressive invasion of misfolded α-syn to the posterior part of the brain. It is unknown whether the administration of human mutant alpha-synuclein (hm-α-syn, a human mutation which occurs in familial PD) into the OB of rats would trigger similar α-syn propagation and subsequently cause pathological changes in broader brain fields associated to PD and establish an animal model of prodromal PD. Methods hm-α-syn was overexpressed in the OB of rats with an AAV injection. Then motor and non-motor symptoms of the SD rats were tested in different behavioral tasks following the AAV injection. In follow-up studies, pathological mechanisms of α-syn spread were explored at the histological, biochemical and micro-structure levels. Results The experimental results indicated that hm-α-syn was overexpressed in the OB 3 weeks after the AAV injection. 1) overexpression of the Hm-α-syn in the OB by the AAV injection could transfer to wider adjacent fields beyond the monosynaptic scope. 2) The number of tyrosine hydroxylase positive cells body and fibers was decreased in the substantia nigra (SN) 12 weeks after AAV injection. This was consistent with decreased levels of the DA neurotransmitter. Importantly, behavioral dysfunctions were found that included olfactory impairment after 3 weeks, motor ability impairment and decreased muscular coordination on a rotarod 6 weeks after the AAV injection.3) The morphological level studies found that the Golgi staining revealed the number of neuronal branches and synapses in the OB, prefrontal cortex (PFC), hippocampus (Hip) and striatum caudate putamen (CPU) were decreased. 4) phosphorylated α-syn, at Ser-129 (pSer129), was found to be increased in hm-α-syn injected animals in comparison to controls that overexpressed GFP alone, which was also found in the most of LB stained by the thioflavine S (ThS) in the SN field. 5) A marker of autophagy (LC3B) was increased in serval fields, which was colacolizated with a marker of apoptosis in the SN field. Conclusions These results demonstrate that expression of exogenous mutant α-syn in the OB induces pathological changes in the sensitive brain fields by transferring pathogenic α-syn to adjacent fields. This method may be useful for establishing an animal model of prodromal PD.http://link.springer.com/article/10.1186/s40035-018-0128-6Alpha-synucleinProdromal animal modelParkinson’s diseaseOlfactory bulbAutophagy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Haichen Niu Lingyu Shen Tongzhou Li Chao Ren Sheng Ding Lei Wang Zhonghai Zhang Xiaoyu Liu Qiang Zhang Deqin Geng Xiujuan Wu Haiying Li |
spellingShingle |
Haichen Niu Lingyu Shen Tongzhou Li Chao Ren Sheng Ding Lei Wang Zhonghai Zhang Xiaoyu Liu Qiang Zhang Deqin Geng Xiujuan Wu Haiying Li Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease Translational Neurodegeneration Alpha-synuclein Prodromal animal model Parkinson’s disease Olfactory bulb Autophagy |
author_facet |
Haichen Niu Lingyu Shen Tongzhou Li Chao Ren Sheng Ding Lei Wang Zhonghai Zhang Xiaoyu Liu Qiang Zhang Deqin Geng Xiujuan Wu Haiying Li |
author_sort |
Haichen Niu |
title |
Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease |
title_short |
Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease |
title_full |
Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease |
title_fullStr |
Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease |
title_full_unstemmed |
Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease |
title_sort |
alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of parkinson’s disease |
publisher |
BMC |
series |
Translational Neurodegeneration |
issn |
2047-9158 |
publishDate |
2018-09-01 |
description |
Abstract Background Parkinson’s disease (PD) is a neurodegenerative disease characterized by intraneuronal Lewy Body (LB) aggregates composed of misfolded alpha-synuclein (α-syn). The spread of misfolded α-syn follows a typical pattern: starting in the olfactory bulb (OB) and the gut, this pathology is followed by the progressive invasion of misfolded α-syn to the posterior part of the brain. It is unknown whether the administration of human mutant alpha-synuclein (hm-α-syn, a human mutation which occurs in familial PD) into the OB of rats would trigger similar α-syn propagation and subsequently cause pathological changes in broader brain fields associated to PD and establish an animal model of prodromal PD. Methods hm-α-syn was overexpressed in the OB of rats with an AAV injection. Then motor and non-motor symptoms of the SD rats were tested in different behavioral tasks following the AAV injection. In follow-up studies, pathological mechanisms of α-syn spread were explored at the histological, biochemical and micro-structure levels. Results The experimental results indicated that hm-α-syn was overexpressed in the OB 3 weeks after the AAV injection. 1) overexpression of the Hm-α-syn in the OB by the AAV injection could transfer to wider adjacent fields beyond the monosynaptic scope. 2) The number of tyrosine hydroxylase positive cells body and fibers was decreased in the substantia nigra (SN) 12 weeks after AAV injection. This was consistent with decreased levels of the DA neurotransmitter. Importantly, behavioral dysfunctions were found that included olfactory impairment after 3 weeks, motor ability impairment and decreased muscular coordination on a rotarod 6 weeks after the AAV injection.3) The morphological level studies found that the Golgi staining revealed the number of neuronal branches and synapses in the OB, prefrontal cortex (PFC), hippocampus (Hip) and striatum caudate putamen (CPU) were decreased. 4) phosphorylated α-syn, at Ser-129 (pSer129), was found to be increased in hm-α-syn injected animals in comparison to controls that overexpressed GFP alone, which was also found in the most of LB stained by the thioflavine S (ThS) in the SN field. 5) A marker of autophagy (LC3B) was increased in serval fields, which was colacolizated with a marker of apoptosis in the SN field. Conclusions These results demonstrate that expression of exogenous mutant α-syn in the OB induces pathological changes in the sensitive brain fields by transferring pathogenic α-syn to adjacent fields. This method may be useful for establishing an animal model of prodromal PD. |
topic |
Alpha-synuclein Prodromal animal model Parkinson’s disease Olfactory bulb Autophagy |
url |
http://link.springer.com/article/10.1186/s40035-018-0128-6 |
work_keys_str_mv |
AT haichenniu alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT lingyushen alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT tongzhouli alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT chaoren alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT shengding alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT leiwang alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT zhonghaizhang alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT xiaoyuliu alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT qiangzhang alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT deqingeng alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT xiujuanwu alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease AT haiyingli alphasynucleinoverexpressionintheolfactorybulbinitiatesprodromalsymptomsandpathologyofparkinsonsdisease |
_version_ |
1725061947780497408 |