THE VAPB-PTPIP51 ER-MITOCHONDRIA TETHERS IN FRONTOTEMPORAL DEMENTIA AND RELATED AMYOTROPHIC LATERAL SCLEROSIS

Abstract

Signaling between the ER and mitochondria regulates many of the neurophysiological functions that are damaged in FTD/ALS. This signaling involves close physical contacts between the two organelles. We showed that the integral ER protein VAPB binds to the outer mitochondrial membrane protein PTPIP51 to mediate these contacts. VAPB and PTPIP51 thus act as molecular scaffolds to tether the two organelles. We have investigated how FTD/ALS insults affect ER-mitochondria contacts and signaling, and the VAPB-PTPIP51 tethers. ER-mitochondria contacts and the VAPB-PTPIP51 interaction were quantified in cell and transgenic mouse models of FTD/ALS. Contacts were quantified by EM and super-resolution microscopy. The VAPB-PTPIP51 interaction was monitored by proximity ligation, immunoprecipitation and dimerization-dependent EGFP fusion assays. Ca2+ imaging was used to determine ER-mitochondria Ca2+ exchange. Signal transduction mechanisms linking FTD/ALS insults with damage to the VAPB-PTPIP51 tethers involved mass spectrometry. FTD/ALS associated TDP-43 and FUS both disrupt ER-mitochondria contacts, Ca2+ exchange and linked mitochondrial ATP production. This disruption involved activation of GSK3beta and breaking of the VAPB-PTPIP51 tethers. Potential GSK3beta phosphorylation sites were identified in both VAPB and PTPIP51. The Sigma-1 receptor was identified as a regulator of the VAPB-PTPIP51 interaction that may be targeted for damage by TDP-43 and FUS. The identification of VAPB and PTPIP51 as tethering proteins enabled the construction of novel drug screens. Damage to ER-mitochondria signaling and the VAPB-PTPIP51 ER-mitochondria tethering proteins is a feature of FTD/ALS. Together these findings identify a new pathogenic process in FTD/ALS that can explain many disease features and which represents a novel therapeutic target.