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Recent advances have revealed common pathological changes in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis with related frontotemporal dementia (ALS/FTD). Many of these changes can be linked to alterations in endoplasmic reticulum (ER)–mitochondria signaling, including dysregulation of Ca2+ signaling, autophagy, lipid metabolism, ATP production, axonal transport, ER stress responses and synaptic dysfunction. ER–mitochondria signaling involves specialized regions of ER, called mitochondria-associated membranes (MAMs). Owing to their role in neurodegenerative processes, MAMs have gained attention as they appear to be associated with all the major neurodegenerative diseases. Furthermore, their specific role within neuronal maintenance is being revealed as mutant genes linked to major neurodegenerative diseases have been associated with damage to these specialized contacts. Several studies have now demonstrated that these specialized contacts regulate neuronal health and synaptic transmission, and that MAMs are damaged in patients with neurodegenerative diseases. This Review will focus on the role of MAMs and ER–mitochondria signaling within neurons and how damage of the ER–mitochondria axis leads to a disruption of vital processes causing eventual neurodegeneration.

The role of microglia during neurodegeneration remains controversial. We investigated whether microglial cells have a neurotoxic or neuroprotective function in the retina. Retinal explants from 10-day-old mice were treated in vitro with minocycline to inhibit microglial activation, with LPS to increase microglial activation, or with liposomes loaded with clodronate (Lip-Clo) to deplete microglial cells. Flow cytometry was used to assess the viability of retinal cells in the explants and the TUNEL method to show the distribution of dead cells. The immunophenotypic and morphological features of microglia and their distribution were analyzed with flow cytometry and immunocytochemistry. Treatment of retinal explants with minocycline reduced microglial activation and simultaneously significantly decreased cell viability and increased the presence of TUNEL-labeled cell profiles. This treatment also prevented the migration of microglial cells towards the outer nuclear layer, where cell death was most abundant. The LPS treatment increased microglial activation but had no effect on cell viability or microglial distribution. Finally, partial microglial removal with Lip-Clo diminished the cell viability in the retinal explants, showing a similar effect to that of minocycline. Hence, cell viability is diminished in retinal explants cultured in vitro when microglial cells are removed or their activation is inhibited, indicating a neurotrophic role for microglia in this system.

Microglial cell precursors located in the area of the base of the pecten and the optic nerve head (BP/ONH) start to enter the retina of quail embryos at the 7th day of incubation (E7), subsequently colonizing the entire retina by central-to-peripheral tangential migration, as previously shown by our group. The present study demonstrates a precise chronological coincidence of the onset of microglial cell entry into the retina with a striking increase in death of retinal cells, as revealed by their active caspase-3 expression and TUNEL staining, in regions dorsal to the BP/ONH area, suggesting that dying retinal cells would contribute to the microglial cell inflow into the retina. However, the molecular mechanisms involved in this inflow are currently unclear. Extracellular nucleotides, such as ATP and UDP, have previously been shown to favor migration of microglia towards brain injuries because they are released by apoptotic cells and stimulate both chemotaxis and chemokinesis in microglial cells via signaling through purinergic receptors. Hence, we tested here the hypothesis that ATP and UDP play a role in the entry and migration of microglial precursors into the developing retina. For this purpose, we used an experimental model system based on organotypic cultures of E6.5 quail embryo retina explants, which mimics the entry and migration of microglial precursors in the in situ developing retina. Inhibition of purinergic signaling by treating retina explants with either apyrase, a nucleotide-hydrolyzing enzyme, or suramin, a broad spectrum antagonist of purinergic receptors, significantly prevents the entry of microglial cells into the retina. In addition, treatment of retina explants with either exogenous ATP or UDP results in significantly increased numbers of microglial cells entering the retina. In light of these findings, we conclude that purinergic signaling by extracellular ATP and UDP is necessary for the entry and migration of microglial cells into the embryonic retina by inducing chemokinesis in these cells.

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many neuronal functions that are perturbed in amyotrophic lateral sclerosis (ALS) and perturbation to ER-mitochondria signaling is seen in cell and transgenic models of ALS. However, there is currently little evidence that ER-mitochondria signaling is altered in human ALS. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and “tether” regions of ER to the mitochondrial surface. The VAPB-PTPI51 tethers are now known to regulate a number of ER-mitochondria signaling functions. These include delivery of Ca2+ from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and ALS spinal cords. We show that VAPB protein levels are reduced in ALS. Proximity ligation assays were then used to quantify the VAPB-PTPIP51 interaction in spinal cord motor neurons in control and ALS cases. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in ALS. Thus, we identify a new pathogenic event in post-mortem ALS.