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Accumulating evidence suggests that neurodegenerative diseases are not merely neuronal in nature but comprise multicellular involvement, with astrocytes emerging as key players. The pathomechanisms of several neurodegenerative diseases involve the deposition of misfolded protein aggregates in neurons that have characteristic prion-like behaviours such as template-directed seeding, intercellular propagation, distinct conformational strains and protein-mediated toxicity. The role of astrocytes in dealing with these pathological prion-like protein aggregates and whether their responses either protect from or conspire with the disease process is currently unclear. Here we review the existing literature implicating astrocytes in multiple neurodegenerative proteinopathies with a focus on prion-like behaviour in this context.

We recently described aberrantly increased cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as new hallmarks of amyotrophic lateral sclerosis (ALS). However, the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep sequencing of nuclear and cytoplasmic fractions of human induced pluripotent stem cells undergoing motor neurogenesis, we reveal that ALS-causing VCP gene mutations lead to compartment-specific aberrant accumulation of IRTs. Specifically, we identify >100 IRTs with increased cytoplasmic abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins. Remarkably, TDP-43, SFPQ and FUS—RNA binding proteins known for nuclear-to-cytoplasmic mislocalization in ALS—abundantly and specifically bind to this aberrant cytoplasmic pool of IRTs. Our data are therefore consistent with a novel role for cytoplasmic IRTs in regulating compartment-specific protein abundance. This study provides new molecular insight into potential pathomechanisms underlying ALS and highlights aberrant cytoplasmic IRTs as potential therapeutic targets., Aberrant cytoplasmic SFPQ intron-retaining transcripts (IRTs) have recently been described in ALS, but their roles remained unclear. Tyzack, Neeves et al. now identify >100 cytoplasmic IRTs and show that they are ‘blueprints’ for ALS-related RNA binding protein mislocalization, as well as potential therapeutic targets.

Clarke and Patani review the involvement of microglia in ALS, focusing specifically on evidence for spatiotemporally regulated neurotoxic and neuroprotective roles. Understanding how microglia contribute to the ‘cellular phase’ of ALS promises to advance the development of therapies with a mechanistic rationale., Microglia are the primary immune cells of the CNS, carrying out key homeostatic roles and undergoing context-dependent and temporally regulated changes in response to injury and neurodegenerative diseases. Microglia have been implicated in playing a role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by extensive motor neuron loss leading to paralysis and premature death. However, as the pathomechansims of ALS are increasingly recognized to involve a multitude of different cell types, it has been difficult to delineate the specific contribution of microglia to disease. Here, we review the literature of microglial involvement in ALS and discuss the evidence for the neurotoxic and neuroprotective pathways that have been attributed to microglia in this disease. We also discuss accumulating evidence for spatiotemporal regulation of microglial activation in this context. A deeper understanding of the role of microglia in the ‘cellular phase’ of ALS is crucial in the development of mechanistically rationalized therapies.

See Vidal and Atkin (doi:10.1093/brain/awz256) for a scientific commentary on this article. ALS remains incurable due to an incomplete understanding of its molecular pathogenesis. Tyzack, Luisier et al. report that FUS protein, previously thought to mislocalise only in patients with FUS mutations, is also mislocalised in many cases of sporadic ALS. They further propose an underlying molecular mechanism for the mislocalisation., Mutations causing amyotrophic lateral sclerosis (ALS) clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins, which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RNA binding proteins mislocalize without necessarily becoming constituents of cytoplasmic inclusions themselves remains relatively unexplored. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RNA binding protein fused in sarcoma (FUS), in an unaggregated state, may occur more widely in ALS than previously recognized. To address this hypothesis, we analysed motor neurons from a human ALS induced-pluripotent stem cell model caused by the VCP mutation. Additionally, we examined mouse transgenic models and post-mortem tissue from human sporadic ALS cases. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and, crucially, in sporadic ALS spinal cord tissue from multiple cases. Furthermore, we provide evidence that FUS protein binds to an aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model for ALS pathogenesis whereby aberrant intron retention in SFPQ transcripts contributes to FUS mislocalization through their direct interaction and nuclear export. In summary, we report widespread mislocalization of the FUS protein in ALS and propose a putative underlying mechanism for this process.

The pathological correlate of clinical disability and progression in multiple sclerosis is neuronal and axonal loss; however, the underlying mechanisms are unknown. Abnormal phosphorylation of tau is a common feature of some neurodegenerative disorders, such as Alzheimer's disease. We investigated the presence of tau hyperphosphorylation and its relationship with neuronal and axonal loss in chronic experimental autoimmune encephalomyelitis (CEAE) and in brain samples from patients with secondary progressive multiple sclerosis. We report the novel finding of abnormal tau phosphorylation in CEAE. We further show that accumulation of insoluble tau is associated with both neuronal and axonal loss that correlates with progression from relapsing-remitting to chronic stages of EAE. Significantly, analysis of secondary progressive multiple sclerosis brain tissue also revealed abnormally phosphorylated tau and the formation of insoluble tau. Together, these observations provide the first evidence implicating abnormal tau in the neurodegenerative phase of tissue injury in experimental and human demyelinating disease.