Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating.

Mutations in the Kv3.3 potassium channel (KCNC3) cause cerebellar neurodegeneration and impair auditory processing. The cytoplasmic C terminus of Kv3.3 contains a proline-rich domain conserved in proteins that activate actin nucleation through Arp2/3. We found that Kv3.3 recruits Arp2/3 to the plasma membrane, resulting in formation of a relatively stable cortical actin filament network resistant to cytochalasin D that inhibits fast barbed end actin assembly. These Kv3.3-associated actin structures are required to prevent very rapid N-type channel inactivation during short depolarizations of the plasma membrane. The effects of Kv3.3 on the actin cytoskeleton are mediated by the binding of the cytoplasmic C terminus of Kv3.3 to Hax-1, an anti-apoptotic protein that regulates actin nucleation through Arp2/3. A human Kv3.3 mutation within a conserved proline-rich domain produces channels that bind Hax-1 but are impaired in recruiting Arp2/3 to the plasma membrane, resulting in growth cones with deficient actin veils in stem cell-derived neurons.

Association between Parkinson's Disease and Cancer: New Findings and Possible Mediators.

Epidemiological evidence points to an inverse association between Parkinson's disease (PD) and almost all cancers except melanoma, for which this association is positive. The results of multiple studies have demonstrated that patients with PD are at reduced risk for the majority of neoplasms. Several potential biological explanations exist for the inverse relationship between cancer and PD. Recent results identified several PD-associated proteins and factors mediating cancer development and cancer-associated factors affecting PD. Accumulating data point to the role of genetic traits, members of the synuclein family, neurotrophic factors, the ubiquitin-proteasome system, circulating melatonin, and transcription factors as mediators. Here, we present recent data about shared pathogenetic factors and mediators that might be involved in the association between these two diseases. We discuss how these factors, individually or in combination, may be involved in pathology, serve as links between PD and cancer, and affect the prevalence of these disorders. Identification of these factors and investigation of their mechanisms of action would lead to the discovery of new targets for the treatment of both diseases.

Cell Responses to Extracellular α-Synuclein.

Synucleins are small naturally unfolded proteins involved in neurodegenerative diseases and cancer. The family contains three members: α-, ß-, and -synuclein. α-Synuclein is the most thoroughly investigated because of its close association with Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy. Until recently, the synuclein's research was mainly focused on their intracellular forms. However, new studies highlighted the important role of extracellular synucleins. Extracellular forms of synucleins propagate between various types of cells, bind to cell surface receptors and transmit signals, regulating numerous intracellular processes. Here we give an update of the latest results about the mechanisms of action of extracellular synucleins, their binding to cell surface receptors, effect on biochemical pathways and the role in neurodegeneration and neuroinflammation.

Controversial Properties of Amyloidogenic Proteins and Peptides: New Data in the COVID Era.

For a long time, studies of amyloidogenic proteins and peptides (amyloidogenic PPs) have been focused basically on their harmful properties and association with diseases. A vast amount of research has investigated the structure of pathogenic amyloids forming fibrous deposits within or around cells and the mechanisms of their detrimental actions. Much less has been known about the physiologic functions and beneficial properties of amyloidogenic PPs. At the same time, amyloidogenic PPs have various useful properties. For example, they may render neurons resistant to viral infection and propagation and stimulate autophagy. We discuss here some of amyloidogenic PPs' detrimental and beneficial properties using as examples beta-amyloid (ß-amyloid), implicated in the pathogenesis of Alzheimer's disease (AD), and α-synuclein-one of the hallmarks of Parkinson's disease (PD). Recently amyloidogenic PPs' antiviral and antimicrobial properties have attracted attention because of the COVID-19 pandemic and the growing threat of other viral and bacterial-induced diseases. Importantly, several COVID-19 viral proteins, e.g., spike, nucleocapsid, and envelope proteins, may become amyloidogenic after infection and combine their harmful action with the effect of endogenous APPs. A central area of current investigations is the study of the structural properties of amyloidogenic PPs, defining their beneficial and harmful properties, and identifying triggers that transform physiologically important amyloidogenic PPs into vicious substances. These directions are of paramount importance during the current SARS-CoV-2 global health crisis.

Phytochemicals as Regulators of Genes Involved in Synucleinopathies.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein aggregates in neurons, nerve fibers or glial cells. Three main types of diseases belong to the synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. All of them develop as a result of an interplay of genetic and environmental factors. Emerging evidence suggests that epigenetic mechanisms play an essential role in the development of synucleinopathies. Since there is no disease-modifying treatment for these disorders at this time, interest is growing in plant-derived chemicals as a potential treatment option. Phytochemicals are substances of plant origin that possess biological activity, which might have effects on human health. Phytochemicals with neuroprotective activity target different elements in pathogenic pathways due to their antioxidants, anti-inflammatory, and antiapoptotic properties, and ability to reduce cellular stress. Multiple recent studies demonstrate that the beneficial effects of phytochemicals may be explained by their ability to modulate the expression of genes implicated in synucleinopathies and other diseases. These substances may regulate transcription directly via transcription factors (TFs) or play the role of epigenetic regulators through their effect on histone modification, DNA methylation, and RNA-based mechanisms. Here, we summarize new data about the impact of phytochemicals on the pathogenesis of synucleinopathies through regulation of gene expression.

ABCA7-A Member of the ABC Transporter Family in Healthy and Ailing Brain.

Identification of genetic markers of a human disease, which is generally sporadic, may become an essential tool for the investigation of its molecular mechanisms. The role of ABCA7 in Alzheimer's disease (AD) was discovered less than ten years ago when meta-analyses provided evidence that rs3764650 is a new AD susceptibility locus. Recent research advances in this locus and new evidence regarding ABCA7 contribution to the AD pathogenesis brought a new understanding of the underlying mechanisms of this disorder. An interesting, up-to-date review article "ABCA7 and Pathogenic Pathways of Alzheimer's Disease" by Aikawa et al. (2018), outlines the ABCA7 role in AD and summarizes new findings in this exciting area. ABC transporters or ATP-binding cassette transporters are a superfamily of proteins belonging to a cell transport system. Currently, members of the family are the focus of attention because of their central role in drug pharmacokinetics. Two recent findings are the reason why much attention is drawn to the ABCA7 family. First, is the biochemical data showing a role of ABCA7 in amyloid pathology. Second, genetic data identifying ABCA7 gene variants as loci responsible for the late-onset AD. These results point to the ABCA7 as a significant new contributor to the pathogenesis of AD.

Amyloidosis and Longevity: A Lesson from Plants.

The variety of lifespans of different organisms in nature is amazing. Although it is acknowledged that the longevity is determined by a complex interaction between hereditary and environmental factors, many questions about factors defining lifespan remain open. One of them concerns a wide range of lifespans of different organisms. The reason for the longevity of certain trees, which reaches a thousand years and exceeds the lifespan of most long living vertebrates by a huge margin is also not completely understood. Here we have discussed some distinguishing characteristics of plants, which may explain their remarkable longevity. Among them are the absence (or very low abundance) of intracellular inclusions composed of amyloidogenic proteins, the lack of certain groups of proteins prone to aggregate and form amyloids in animals, and the high level of compounds which inhibit protein aggregation and possess antiaging properties.

Synucleins and Gene Expression: Ramblers in a Crowd or Cops Regulating Traffic?

Synuclein family consists of three members, α, ß, and γ-synuclein. Due to their involvement in human diseases, they have been thoroughly investigated for the last 30 years. Since the first synuclein identification and description, members of this family are found in all vertebrates. Sequencing of their genes indicates high evolutionary conservation suggesting important function(s) of these proteins. They are small naturally unfolded proteins prone to aggregate, easily change their conformation, and bind to the membranes. The genes for α, ß, and γ-synuclein have different chromosomal localization and a well preserved general organization composed of five coding exons of similar size. Three genes encoding synucleins are present in the majority of vertebrates, however, a variable number of synuclein genes are described in fishes of different species. An important question concerns their normal function in cells and tissues. α-Synuclein is implicated in the regulation of synaptic activity through regulation of synaptic vesicle release, while the physiological functions of two other members of the family is understood less clearly. Here we discuss recent results describing their role in the regulation of gene expression.