RNA-binding protein dysfunction in neurodegeneration

Protein homeostasis (proteostasis) is a prerequisite for cellular viability and plasticity. In particular, post-mitotic cells such as neurons rely on a tightly regulated safeguard system that allows for regulated protein expression. Previous investigations have identified RNA-binding proteins (RBPs) as crucial regulators of protein expression in nerve cells. However, during neurodegeneration, their ability to control the proteome is progressively disrupted. In this review, we examine the malfunction of key RBPs such as TAR DNA-binding protein 43 (TDP-43), Fused in Sarcoma (FUS), Staufen, Pumilio and fragile-X mental retardation protein (FMRP). Therefore, we focus on two key aspects of RBP dysfunctions in neurodegeneration: protein aggregation and dysregulation of their target RNAs. Moreover, we discuss how the chaperone system responds to changes in the RBP-controlled transcriptome. Based on recent findings, we propose a two-hit model in which both, harmful RBP deposits and target mRNA mistranslation contribute to neurodegeneration observed in RBPathologies.

Vesicular dysfunction and pathways to neurodegeneration

Cellular control of vesicle biology and trafficking is critical for cell viability, with disruption of these pathways within the cells of the central nervous system resulting in neurodegeneration and disease. The past two decades have provided important insights into both the genetic and biological links between vesicle trafficking and neurodegeneration. In this essay, the pathways that have emerged as being critical for neuronal survival in the human brain will be discussed – illustrating the diversity of proteins and cellular events with three molecular case studies drawn from different neurological diseases.

Tau aggregation and its relation to selected forms of neuronal cell death

How neurons die in neurodegenerative diseases is still unknown. The distinction between apoptosis as a genetically controlled mechanism, and necrosis, which was viewed as an unregulated process, has blurred with the ever-increasing number of necrotic-like death subroutines underpinned by genetically defined pathways. It is therefore pertinent to ask whether any of them apply to neuronal cell death in tauopathies. Although Alzheimer’s disease (AD) is the most prevalent tauopathy, tauopathies comprise an array of over 30 diseases in which the cytoplasmic protein tau aggregates in neurons, and also, in some diseases, in glia. Animal models have sought to distil the contribution of tau aggregation to the cell death process but despite intensive research, no one mechanism of cell death has been unequivocally defined. The process of tau aggregation, and the fibrillar structures that form, touch on so many cellular functions that there is unlikely to be a simple linear pathway of death; as one is blocked another is likely to take the lead. It is timely to ask how far we have advanced into defining whether any of the molecular players in the new death subroutines participate in the death process. Here we briefly review the currently known cell death routines and explore what is known about their participation in tau aggregation-related cell death. We highlight the involvement of cell autonomous and the more recent non-cell autonomous pathways that may enhance tau-aggregate toxicity, and discuss recent findings that implicate microglial phagocytosis of live neurons with tau aggregates as a mechanism of death.

LRRK2 signaling in neurodegeneration: two decades of progress

Leucine-rich repeat kinase 2 (LRRK2) is a complex GTPase/kinase orchestrating cytoskeletal dynamics and multiple steps of the endolysosomal pathway through interaction with a host of partners and phosphorylation of a subset of Rab GTPases. Mutations in LRRK2 cause late-onset Parkinson’s disease (PD) and common variants in the locus containing LRRK2 have been associated with sporadic PD, progressive supranuclear palsy as well as a number of inflammatory diseases. This review encompasses the major discoveries in the field of LRRK2 pathobiology, from the initial gene cloning to the latest progress in LRRK2 inhibition as a promising therapeutic approach to fight neurodegeneration.

PINK1 signalling in neurodegenerative disease

PTEN-induced kinase 1 (PINK1) impacts cell health and human pathology through diverse pathways. The strict processing of full-length PINK1 on the outer mitochondrial membrane populates a cytoplasmic pool of cleaved PINK1 (cPINK1) that is constitutively degraded. However, despite rapid proteasomal clearance, cPINK1 still appears to exert quality control influence over the neuronal protein homeostasis network, including protein synthesis and degradation machineries. The cytoplasmic concentration and activity of this molecule is therefore a powerful sensor that coordinates aspects of mitochondrial and cellular health. In addition, full-length PINK1 is retained on the mitochondrial membrane following depolarisation, where it is a powerful inducer of multiple mitophagic pathways. This function is executed primarily through the phosphorylation of several ubiquitin ligases, including its most widely studied substrate Parkin. Furthermore, the phosphorylation of both pro- and anti-apoptotic proteins by mitochondrial PINK1 acts as a pro-cellular survival signal when faced with apoptotic stimuli. Through these varied roles PINK1 directly influences functions central to cell dysfunction in neurodegenerative disease.

Targeted proteolytic products of τ and α-synuclein in neurodegeneration

CNS pathological inclusions comprising τ or α-synuclein (αSyn) define a spectrum of neurodegenerative diseases, and these can often present concurrently in the same individuals. The aggregation of both proteins is clearly associated with neurodegeneration and the deleterious properties of each protein is further supported by mutations in each gene (MAPT and SNCA, respectively) resulting in disease. The initiating events in most sporadic neurodegenerative diseases are still unclear but growing evidence suggests that the aberrant proteolytic cleavage of τ and αSyn results in products that can be toxic and/or initiate aggregation that can further spread by a prion-like mechanism. The accumulation of some of these cleavage products can further potentiate the progression of protein aggregation transmission and lead to their accumulation in peripheral biofluids such as cerebrospinal fluid (CSF) and blood. The future development of new tools to detect specific τ and αSyn abnormal cleavage products in peripheral biofluids could be useful biomarkers and better understand of the role of unique proteolytic activities could yield therapeutic interventions.

Inflammasome activation in neurodegenerative diseases

Approximately ten million people are diagnosed with dementia annually since they experience difficulties with memory and thinking skills. Since neurodegenerative diseases are diagnosed late, most of them are difficult to treat. This is due to the increased severity of the disease during the progression when neuroinflammation plays a critical role. The activation of immune cells, especially microglia, plays a crucial role in the development of neurodegenerative diseases. Molecular sensors within these microglia, such as the NLRP3 inflammasome, are activated by signals that represent the hallmarks of neurodegenerative diseases. Here, we first summarize the two activation steps of NLRP3 inflammasome activation. Furthermore, we discuss the key factors that contribute to NLRP3 inflammasome activation in the different neuroinflammatory diseases, like Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). The prominent NLRP3 inflammasome triggers include amyloid β and tau oligomers in AD, α-synuclein in PD, and superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP43) in ALS. NLRP3 inhibitor treatment has shown promising results in several preclinical mouse models of AD, PD, and ALS. Finally, we postulate that current understandings underpin the potential for NLRP3 inhibitors as a therapeutic target in neurodegenerative diseases.

Cryo-EM structures of τ filaments from human brain

Electron cryo-microscopy (cryo-EM) has made it possible to determine near-atomic structures of τ filaments from human brain. Previous work had shown that the cores of paired helical and straight filaments of Alzheimer’s disease are made of two identical, but differently arranged C-shaped protofilaments. In recent years, cryo-EM has shown that the Alzheimer τ fold is 79 amino acids long. Five of the eight β-strands give rise to two antiparallel β-sheets, with the other three forming a β-helix. High-affinity binding sites of positron emission tomography ligand APN-1607 (PM-PBB3) are in the β-helix region. The Alzheimer fold contrasts with the 94 amino acid-long Pick fold, which is J-shaped and comprises nine β-strands that give rise to four antiparallel β-sheets, in the absence of a β-helix. Chronic traumatic encephalopathy τ fold is similar to the Alzheimer fold, but differs in the β-helix region, which is larger and contains a non-proteinaceous density that is probably hydrophobic. These folds are mostly two-layered. By contrast, the 107 amino acid τ fold of the 4R tauopathy corticobasal degeneration is four-layered and comprises 11 β-strands. It contains an internal, probably hydrophilic, density that is surrounded by τ. The τ folds described here share the presence of microtubule-binding repeats 3 and 4, as well as 10–13 amino acids after repeat 4.

Nuclear receptors: from molecular mechanisms to therapeutics

Nuclear receptors are classically defined as ligand-activated transcription factors that regulate key functions in reproduction, development, and physiology. Humans have 48 nuclear receptors, which when dysregulated are often linked to diseases. Because most nuclear receptors can be selectively activated or inactivated by small molecules, they are prominent therapeutic targets. The basic understanding of this family of transcription factors was accelerated in the 1980s upon the cloning of the first hormone receptors. During the next 20 years, a deep understanding of hormone signaling was achieved that has translated to numerous clinical applications, such as the development of standard-of-care endocrine therapies for hormonally driven breast and prostate cancers. A 2004 issue of this journal reviewed progress on elucidating the structures of nuclear receptors and their mechanisms of action. In the current issue, we focus on the broad application of new knowledge in this field for therapy across diverse disease states including cancer, cardiovascular disease, various inflammatory diseases, the aging brain, and COVID-19.

Estrogen receptors and the aging brain

The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor subtype and upstream or downstream effectors, can mediate gene transcription and rapid non-genomic actions. In this way, estrogen receptors in the brain participate in modulating neural differentiation, proliferation, neuroinflammation, cholesterol metabolism, synaptic plasticity, and behavior. Circulating sex hormones decrease in the course of aging, more rapidly at menopause in women, and slower in men. This review will discuss what this drop entails in terms of modulating neuroprotection and resilience in the aging brain downstream of spatiotemporal estrogen receptor alpha (ERα) and beta (ERβ) signaling, as well as in terms of the sex differences observed in Alzheimer’s disease (AD) and Parkinson’s disease (PD). In addition, controversies related to ER expression in the brain will be discussed. Understanding the spatiotemporal signaling of sex hormones in the brain can lead to more personalized prevention strategies or therapies combating neurodegenerative diseases.