α-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals.
α-Synuclein (α-syn) missense and multiplication mutations have been suggested to cause neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies. Before causing the progressive neuronal loss, α-syn mutations impair exocytosis, which may contribute to eventual neurodegeneration. To understand how α-syn mutations impair exocytosis, we developed a mouse model that selectively expressed PD-related human α-syn A53T (h-α-synA53T) mutation at the calyx of Held terminals, where release mechanisms can be dissected with a patch-clamping technique. With capacitance measurement of endocytosis, we reported that h-α-synA53T, either expressed transgenically or dialyzed in the short term in calyces, inhibited two of the most common forms of endocytosis, the slow and rapid vesicle endocytosis at mammalian central synapses. The expression of h-α-synA53Tin calyces also inhibited vesicle replenishment to the readily releasable pool. These findings may help to understand how α-syn mutations impair neurotransmission before neurodegeneration.


CONCLUSIONS
α-Synuclein (α-syn) missense or multiplication mutations may cause neurodegenerative diseases, such as Parkinson's disease and dementia with Lewy bodies. The initial impact of α-syn mutations before neuronal loss is impairment of exocytosis, which may contribute to eventual neurodegeneration. The mechanism underlying impairment of exocytosis is poorly understood. Here we report that an α-syn mutant, the human α-syn A53T, inhibited two of the most commonly observed forms of endocytosis, slow and rapid endocytosis, at a mammalian central synapse. We also found that α-syn A53T inhibited vesicle replenishment to the readily releasable pool. These results may contribute to accounting for the widely observed early synaptic impairment caused by α-syn mutations in the progression toward neurodegeneration.
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, Georgia 30912, jxu1@gru.edu caih@mail.nih.gov.
Jianhua
http://orcid.org/0000-0003-0084-8856
J
Xu
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Xin-Sheng
XS
Wu
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Jiansong
J
Sheng
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Zhen
Z
Zhang
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, Georgia 30912.
Hai-Yuan
HY
Yue
National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, and.
Lixin
L
Sun
National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, and.
Carmelo
C
Sgobio
National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, and.
Xian
X
Lin
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Shiyong
http://orcid.org/0000-0003-0697-3674
S
Peng
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Yinghui
Y
Jin
Flaum Eye Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
Lin
L
Gan
National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, and jxu1@gru.edu caih@mail.nih.gov.
Huaibin
H
Cai
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Ling-Gang
LG
Wu
D000818:Animals; D001933:Brain Stem / Q000502:physiology; D004705:Endocytosis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009411:Nerve Endings / Q000502:physiology*; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
C497604:SNCA protein, human; D051844:alpha-Synuclein
Parkinson's disease; endocytosis; nerve terminal; transmitter; vesicle; α-synuclein