Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy

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

Neurobiology of Disease (Mar 2023)

Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy

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

Affiliations

Suzhen Lin: Institute of Neurology, Ruijing Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
André D.G. Leitão: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Savannah Fang: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Yingli Gu: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Sophia Barber: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Rhiannon Gilliard-Telefoni: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Alfredo Castro: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Kijung Sung: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Ruinan Shen: Institute of Neurology, Ruijing Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Jazmin B. Florio: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Michael L. Mante: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Jianqing Ding: Institute of Neurology, Ruijing Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
Brian Spencer: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Eliezer Masliah: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Robert A. Rissman: Department 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.
Chengbiao Wu: 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.

Journal volume & issue: Vol. 178
p. 106010

Abstract

Read online

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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

About the journal

Abstract

Keywords