Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

No abstract

Psoriasis is a common, chronic skin disorder, the pathogenesis of which is incompletely understood. Results from various clinical and experimental studies indicate that psoriasis is a complex, multifactorial disease with a genetic predisposition. Factors such as climate, physical trauma, drug, stress and infections (Streptococcus, human immunodeficiency virus) are known to trigger psoriasis. The success of treatment of psoriasis with T-cell depletion and antitumour necrosis factor (TNF)-alpha treatment is explained by the involvement of T cells and TNF- alpha in the pathogenesis of psoriasis. The biochemical basis for the pathogenesis of psoriasis can be attributed to both overexpression and underexpression of certain proteins in psoriatic lesions. The anomalies in protein expression can be classified as abnormal keratinocyte differentiation, keratinocyte hyperproliferation and inflammation. Oxidative stress (OS) and increased free-radical generation have been linked to skin inflammation in psoriasis. The review presents evidence for various markers of psoriasis that can be targeted for effective treatment, including biomarkers of inflammation, keratinocyte hyperproliferation and abnormal differentiation, and stress.

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Prion disease, Huntington's disease, and amyotrophic lateral sclerosis are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation in selected brain regions. The aggregates usually consist of insoluble fibrillar aggregates containing misfolded protein with β-sheet conformation. The most probable explanation is that inclusions and the aggregates symbolize an end stage of a molecular cascade of several events, and that earlier event in the cascade may be more directly tied up to pathogenesis than the inclusions themselves. Small intermediates termed as 'soluble oligomers' in the aggregation process might influence synaptic dysfunction, whereas large, insoluble deposits might function as reservoir of the bioactive oligomers. Compelling evidence suggests the role of misfolded proteins in the form of oligomers might lead to synaptic dysfunction, neuronal apoptosis and brain damage. However, the mechanism by which oligomers trigger neurodegeneration still remains mysterious. The aim of this article is to review the literature around the molecular mechanism and role of oligomers in neurodegeneration and leading approaches toward rational therapeutics.

The toxicity of α-synuclein in the neuropathology of Parkinson's disease which includes its hallmark aggregation has been studied scrupulously in the last decade. Although little is known regarding the normal functions of α-synuclein, its association with membrane phospholipids suggests its potential role in signaling pathways. Following extensive evidences for its nuclear localization, we and others recently demonstrated DNA binding activity of α-synuclein that modulates its conformation as well as aggregation properties. Furthermore, we also underscored the similarities among various amyloidogenic proteins involved in neurodegenerative diseases including amyloid beta peptides and tau. Our more recent studies show that α-synuclein is glycated and glycosylated both in vitro and in neurons, significantly affecting its folding, oligomeric, and DNA binding properties. Glycated α-synuclein causes increased genome damage both via its direct interaction with DNA and by increased generation of reactive oxygen species as glycation byproduct. In this review, we discuss the mechanisms of glycation and other posttranslational modifications of α-synuclein, including phosphorylation and nitration, and their role in neuronal death in Parkinson's disease.

No abstract

Rao et al. Immune Enhancement to Combat COVID-19 consuming nutritional supplements that enhance the immune system. We recommend clinical studies to validate AFO-202 beta glucan in COVID-19 patients to prove its efficacy in overcoming a hyper-inflammation status, thus reducing the mortality, until a definite vaccine is made available.

No abstract