Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases

Abstract

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many of the seemingly disparate physiological functions that are damaged in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). A number of studies have now demonstrated that ER-mitochondria signaling is perturbed in these diseases and there is evidence that this may be a driving mechanism in disease onset and progression. VAPB and PTPIP51 are ER-mitochondria tethering proteins; VAPB is an ER protein and PTPIP51 is an outer mitochondrial membrane protein and the two proteins interact to enable inter-organelle signaling. The VAPB-PTPIP51 interaction is disrupted in Alzheimer's disease, Parkinson's disease, FTD and ALS. Here we review the roles of VAPB and PTPIP51 in ER-mitochondria signaling and the mechanisms by which neurodegenerative disease insults may disrupt the VAPB-PTPIP51 interaction.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Frontotemporal dementia; Neurodegenerative diseases; Parkinson’s disease.

Fig. 1

Representative EM images of ER-mitochondria contact sites in a control transfected NSC-34 motor neuron cell (left) and in an NSC-34 cell transfected with both VAPB and PTPIP51 (right). VAPB and PTPIP51 transfection dramatically increases ER − mitochondria contacts (see orange loops) and high magnification images reveal the presence of structures connecting the two organelles which may correspond to VAPB-PTPIP51 tethers (see red arrowheads)

Fig. 2

Domain structure of human VAPB, VAPA and PTPIP51 with amino acid numbers indicated (the shorter 249 amino acid VAPA isoform is shown). VAPB and VAPA MSP and coiled-coil domains are shown along with their C-terminal transmembrane ER targeting sequences (TM). PTPIP51 N-terminal transmembrane mitochondrial targeting sequence (TM), coiled-coil domain, FFAT motif (VYFTASS) and C-terminal tetratricopeptide repeat domain are all shown

Fig. 3

Neurodegenerative disease insults disrupt the VAPB-PTPIP51 interaction and synaptic function. Parkinson’s disease α-synuclein associates with VAPB to inhibit its binding to PTPIP51. FTD/ALS and Alzheimer’s disease associated TDP43, FUS, C9orf72-derived toxic DPRs and Tau all activate GSK3β which in turn disrupts binding of VAPB to PTPIP51. Breaking of the VAPB-PTPIP51 tethers perturbs ER-mitochondria signaling involving reduced IP3 receptor delivery of Ca²⁺ to mitochondria and damaged lipid metabolism which then leads to synaptic dysfunction and neurodegeneration. Solid lines depict known and dashed lines unknown pathways