Endophilin-A/SH3GL2 calcium switch for synaptic autophagy induction is impaired by a Parkinson’s risk variant

Decet M(1)(2), Soukup SF(3).

Author information:
(1)VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
(2)Department of Neurosciences, Leuven Brain Institute, Mission Lucidity, KU
Leuven, Leuven, Belgium.
(3)Univ. Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France.

At the synapse, proteins are reused several times during neuronal activity,
causing a decline in protein function over time. Although emerging evidence
supports a role of autophagy in synaptic function, the precise molecular
mechanisms linking neuronal activity, autophagy and synaptic dysfunction are
vastly unknown. We show how extracellular calcium influx in the pre-synaptic
terminal constitutes the initial stimulus for autophagosome formation in
response to neuronal activity. This mechanism likely acts to rapidly support
synaptic homeostasis and protein quality control when intense neuronal activity
challenges the synaptic proteome. We identified a residue in the flexible region
of EndoA (Endophilin A) that dictates calcium-dependent EndoA mobility from the
plasma membrane to the cytosol, where this protein interacts with autophagic
membranes to promote autophagosome formation. We discovered that a novel
Parkinson’s disease-risk mutation in SH3GL2 (SH3 domain containing GRB2 like 2,
endophilin A1) disrupts the calcium sensing of SH3GL2, leading to an immobile
protein that cannot respond to calcium influx and therefore disrupting autophagy
induction at synapses. Our work shows how neuronal activity is connected with
autophagy to maintain synaptic homeostasis and survival.

 

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