Abstract
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions. This signaling involves close physical contacts between the two organelles that are mediated by “tethering proteins” that function to recruit regions of ER to the mitochondrial surface. The ER protein, vesicle-associated membrane protein-associated protein B (VAPB) and the mitochondrial membrane protein, protein tyrosine phosphatase interacting protein-51 (PTPIP51), interact to form one such tether. Recently, damage to ER-mitochondria signaling involving disruption of the VAPB-PTPIP51 tethers has been linked to the pathogenic process in Parkinson’s disease, fronto-temporal dementia (FTD) and related amyotrophic lateral sclerosis (ALS). Loss of neuronal synaptic function is a key feature of Parkinson’s disease and FTD/ALS but the roles that ER-mitochondria signaling and the VAPB-PTPIP51 tethers play in synaptic function are not known. Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. Moreover, siRNA loss of VAPB or PTPIP51 perturbs synaptic function and dendritic spine morphology. Our results reveal a new role for the VAPB-PTPIP51 tethers in neurons and suggest that damage to ER-mitochondria signaling contributes to synaptic dysfunction in Parkinson’s disease and FTD/ALS.
Highlights
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a variety of fundamental cellular processes
To identify vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein-51 (PTPIP51) in presynaptic regions, neurons were immunostained for phosphorylated neurofilament heavy chain (NFH) to identify axons, synaptophysin and either VAPB or PTPIP51
To identify VAPB and PTPIP51 in postsynaptic regions, neurons were immunostained for microtubule-associated protein-2 (MAP2) to identify dendrites, Post synaptic density protein-95 (PSD95) and either VAPB or PTPIP51
Summary
Signaling between the ER and mitochondria regulates a variety of fundamental cellular processes These include energy metabolism, Ca2+ homeostasis, phospholipid synthesis, mitochondrial biogenesis and trafficking, ER stress responses, autophagy and inflammation [7, 34, 37, 39]. This signaling is facilitated by close physical contacts between the two organelles such that up to approximately 20% of the mitochondrial surface is closely apposed (10–30 nm distances) to ER membranes. The VAPB-PTPIP51 tethers are known to facilitate inositol 1,4,5-trisphosphate (IP3) receptor mediated delivery of Ca2+ from ER stores to mitochondria, mitochondrial ATP production and autophagy, all of which are known to be regulated by ER-mitochondria crosstalk [9, 13, 33, 45, 46]
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