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Presynaptic Endosomal Cathepsin D Regulates the Biogenesis of GABAergic Synaptic Vesicles.

Abstract：

:Presynaptic endosomes reportedly participate in synaptic vesicle (SV) recycling. However, it remains unclear whether they differentially regulate SV biogenesis and synaptic transmission in different types of synapses and how they are implicated in diseases. Using cryo-electron tomography and endocytic tracing, we uncover different endocytic modes and dynamics associated with distinct SV morphology between glutamatergic and GABAergic synapses. We further find that cathepsin D (CatD), a lysosomal storage disease (LSD) protein, is selectively located in GABAergic presynaptic endosomes. Inactivation of CatD results in enlarged presynaptic endosomes, reduces the readily releasable pool, and impairs synaptic transmission in GABAergic, but not glutamatergic, synapses. Moreover, CatD-deficient mice exhibit hyperactivity and increased sensitivity to seizure, mimicking epileptic behavior in CatD-related LSD patients. These data reveal an important role for presynaptic endosomal CatD in regulating GABAergic SV biogenesis and provide mechanistic insights for understanding the synaptic pathology and behavioral defects in CatD-associated LSD.

journal_name

Cell Rep

journal_title

Cell reports

authors

Li X,Qin L,Li Y,Yu H,Zhang Z,Tao C,Liu Y,Xue Y,Zhang X,Xu Z,Wang Y,Lou H,Tan Z,Saftig P,Chen Z,Xu T,Bi G,Duan S,Gao Z

doi

10.1016/j.celrep.2019.06.006

subject

Has Abstract

pub_date

2019-07-23 00:00:00

pages

1015-1028.e5

issue

4

issn

2211-1247

pii

S2211-1247(19)30764-8

journal_volume

28

pub_type

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