The Interplay Between Autophagy and RNA Homeostasis: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Amyotrophic lateral sclerosis and frontotemporal dementia are neurodegenerative disorders that lie on a disease spectrum, sharing genetic causes and pathology, and both without effective therapeutics. Two pathways that have been shown to play major roles in disease pathogenesis are autophagy and RNA homeostasis. Intriguingly, there is an increasing body of evidence suggesting a critical interplay between these pathways. Autophagy is a multi-stage process for bulk and selective clearance of malfunctional cellular components, with many layers of regulation. Although the majority of autophagy research focuses on protein degradation, it can also mediate RNA catabolism. ALS/FTD-associated proteins are involved in many stages of autophagy and autophagy-mediated RNA degradation, particularly converging on the clearance of persistent pathological stress granules. In this review, we will summarise the progress in understanding the autophagy-RNA homeostasis interplay and how that knowledge contributes to our understanding of the pathobiology of ALS/FTD.

Review: Modelling the pathology and behaviour of frontotemporal dementia.

Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease-causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP-43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide-ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease-relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease-relevance of findings and thus better inform therapeutic development.

Ion channels in epilepsy.

Neuronal excitability is determined by the flux of ions through ion channels. Many types of ion channels are expressed in the central nervous system, each responsible for its own aspect of neuronal excitability, from postsynaptic depolarization to action potential generation to neurotransmitter release. These mechanisms are tightly regulated to create a balance between excitation and inhibition. Disruption of this balance is thought to be key in many neurological disorders, including epilepsy syndromes. More and more ion channel mutations are being identified through genetic studies; however, their incidence is still small, suggesting the presence of undiscovered mutations or other causative mechanisms. Understanding wild-type channel function during epileptic activity may also provide vital insights into the remaining idiopathic epilepsies and provide targets for future antiepileptic drugs.

The role of GABAA receptor biogenesis, structure and function in epilepsy.

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (gamma-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with alpha and beta subunits being the minimal requirement, and the incorporation of a gamma subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.