Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy
Mutations or triplication of the alpha synuclein (ASYN) gene contribute to synucleinopathies including Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent evidence suggests that ASYN also plays an important role in amyloid-induced neurotoxicity, a...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123000244 |
| _version_ | 1811165434288799744 |
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| author | Suzhen Lin André D.G. Leitão Savannah Fang Yingli Gu Sophia Barber Rhiannon Gilliard-Telefoni Alfredo Castro Kijung Sung Ruinan Shen Jazmin B. Florio Michael L. Mante Jianqing Ding Brian Spencer Eliezer Masliah Robert A. Rissman Chengbiao Wu |
| author_facet | Suzhen Lin André D.G. Leitão Savannah Fang Yingli Gu Sophia Barber Rhiannon Gilliard-Telefoni Alfredo Castro Kijung Sung Ruinan Shen Jazmin B. Florio Michael L. Mante Jianqing Ding Brian Spencer Eliezer Masliah Robert A. Rissman Chengbiao Wu |
| author_sort | Suzhen Lin |
| collection | DOAJ |
| description | Mutations or triplication of the alpha synuclein (ASYN) gene contribute to synucleinopathies including Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent evidence suggests that ASYN also plays an important role in amyloid-induced neurotoxicity, although the mechanism(s) remains unknown. One hypothesis is that accumulation of ASYN alters endolysosomal pathways to impact axonal trafficking and processing of the amyloid precursor protein (APP). To define an axonal function for ASYN, we used a transgenic mouse model of synucleinopathy that expresses a GFP-human ASYN (GFP-hASYN) transgene and an ASYN knockout (ASYN−/−) mouse model. Our results demonstrate that expression of GFP-hASYN in primary neurons derived from a transgenic mouse impaired axonal trafficking and processing of APP. In addition, axonal transport of BACE1, Rab5, Rab7, lysosomes and mitochondria were also reduced in these neurons. Interestingly, axonal transport of these organelles was also affected in ASYN−/− neurons, suggesting that ASYN plays an important role in maintaining normal axonal transport function. Therefore, selective impairment of trafficking and processing of APP by ASYN may act as a potential mechanism to induce pathological features of Alzheimer's disease (AD) in PD patients. |
| first_indexed | 2024-04-10T15:37:05Z |
| format | Article |
| id | doaj.art-ce172def23994913ad183ff932d3046b |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-10T15:37:05Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-ce172def23994913ad183ff932d3046b2023-02-13T04:06:53ZengElsevierNeurobiology of Disease1095-953X2023-03-01178106010Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathySuzhen Lin0André D.G. Leitão1Savannah Fang2Yingli Gu3Sophia Barber4Rhiannon Gilliard-Telefoni5Alfredo Castro6Kijung Sung7Ruinan Shen8Jazmin B. Florio9Michael L. Mante10Jianqing Ding11Brian Spencer12Eliezer Masliah13Robert A. Rissman14Chengbiao Wu15Institute of Neurology, Ruijing Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Department of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USAInstitute of Neurology, Ruijing Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Department of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USAInstitute of Neurology, Ruijing Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, ChinaDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USADepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA; VA San Diego Health System, La Jolla, CA, USA; Corresponding authors at: Department of Neurosciences, University of California San Diego, Medical Teaching Facility, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA.Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Corresponding authors at: Department of Neurosciences, University of California San Diego, Medical Teaching Facility, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA.Mutations or triplication of the alpha synuclein (ASYN) gene contribute to synucleinopathies including Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent evidence suggests that ASYN also plays an important role in amyloid-induced neurotoxicity, although the mechanism(s) remains unknown. One hypothesis is that accumulation of ASYN alters endolysosomal pathways to impact axonal trafficking and processing of the amyloid precursor protein (APP). To define an axonal function for ASYN, we used a transgenic mouse model of synucleinopathy that expresses a GFP-human ASYN (GFP-hASYN) transgene and an ASYN knockout (ASYN−/−) mouse model. Our results demonstrate that expression of GFP-hASYN in primary neurons derived from a transgenic mouse impaired axonal trafficking and processing of APP. In addition, axonal transport of BACE1, Rab5, Rab7, lysosomes and mitochondria were also reduced in these neurons. Interestingly, axonal transport of these organelles was also affected in ASYN−/− neurons, suggesting that ASYN plays an important role in maintaining normal axonal transport function. Therefore, selective impairment of trafficking and processing of APP by ASYN may act as a potential mechanism to induce pathological features of Alzheimer's disease (AD) in PD patients.http://www.sciencedirect.com/science/article/pii/S0969996123000244Alzheimer's diseaseParkinson's diseaseAlpha synucleinAPPRab5Rab7 |
| spellingShingle | Suzhen Lin André D.G. Leitão Savannah Fang Yingli Gu Sophia Barber Rhiannon Gilliard-Telefoni Alfredo Castro Kijung Sung Ruinan Shen Jazmin B. Florio Michael L. Mante Jianqing Ding Brian Spencer Eliezer Masliah Robert A. Rissman Chengbiao Wu Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy Neurobiology of Disease Alzheimer's disease Parkinson's disease Alpha synuclein APP Rab5 Rab7 |
| title | Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy |
| title_full | Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy |
| title_fullStr | Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy |
| title_full_unstemmed | Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy |
| title_short | Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy |
| title_sort | overexpression of alpha synuclein disrupts app and endolysosomal axonal trafficking in a mouse model of synucleinopathy |
| topic | Alzheimer's disease Parkinson's disease Alpha synuclein APP Rab5 Rab7 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123000244 |
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