SUMMARY Huntington disease (HD) is caused by a CAG·CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other poly-glutamine diseases.

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Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). In cells, structured CAG, CCUG, CAGG, and G4C2 expansion RNAs activate PKR, which leads to increased levels of multiple RAN proteins. Blocking PKR using PKR-K296R, the TAR RNA binding protein or PKR-KO cells, reduces RAN protein levels. p-PKR is elevated in C9orf72 ALS/FTD human and mouse brains, and inhibiting PKR in C9orf72 BAC transgenic mice using AAV-PKR-K296R or the Food and Drug Administration (FDA)-approved drug metformin, decreases RAN proteins, and improves behavior and pathology. In summary, targeting PKR, including by use of metformin, is a promising therapeutic approach for C9orf72 ALS/FTD and other expansion diseases.

Highlights d Human antibodies recognize GA or GP RAN proteins with high affinity and selectivity d Human antibodies cross the blood-brain barrier and engage RAN protein targets in vivo d a-GA 1 antibody reduces GA, GP, and GR levels in C9 models d a-GA 1 improves behavior and survival and decreases neurodegeneration in C9-BAC mice

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Oxidative stress has been implicated in the etiology of neurodegenerative diseases and aging. Indeed, accumulation of reactive oxygen species, such as hydrogen peroxide, generated by inflammatory cells, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders of the central nervous system, such as Alzheimer's disease. The present study indicates that H(2)O(2)-induced cell death can be inhibited in the presence of 1,2,4-triazine derivatives, as measured by MTT and caspase-3 activity. We further show that these compounds exert their protective effect by up-regulation of hemeoxygenase-1, glutamylcysteine synthetase, glutathione peroxidase and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), while they inhibit NF-kappaB and decrease lipid peroxidation. It shows that there is a potential cross talk between NF-kappaB and Nrf2, an important cytoprotective transcription factor in the presence of these compounds. Moreover, in order for drugs to be effective in the treatment of neurodegenerative diseases, they must be capable of penetrating the blood-brain barrier, whereas more than 98% of all potential central nervous system drugs don't cross. Using a reliable model based on the artificial neural network indicated that these compounds satisfy this requirement.

Increased oxidative stress is widely accepted to be a factor in the development and progression of Alzheimer's disease (AD). Here we introduced Salvia sahendica as a protective agent in differentiated PC12 cells, which are commonly considered to be a reliable model of neuronal cells. Our results demonstrated that S. sahendica has antioxidant and antiglycating properties in in vitro system and these properties are expanded into H(2)O(2)-induced model. S. sahendica inhibited H(2)O(2)-induced cell death in PC12 cells. We further showed that this plant exerts its protective effect by increasing superoxide dismutase and catalase levels, reducing lipid peroxidation and upregulating hemoxygenase-1 and glutamylcysteine synthetase proteins. This study raises the possibility of developing S. sahendica as a potential neuroprotective agent.

This study was designed to examine antioxidant activities, antiglycating abilities and neuroprotective effects of methanolic extracts of Salvia choloroleuca, Salvia santolinifolia and Salvia mirzayanii from Iran. The extracts were screened for their possible antioxidant activities by several biochemical assays such as DPPH, FRAP, β-carotene bleaching and TEAC assays. HPLC analysis of these extracts led to the separation of a number of components such as catechine and rosmarinic acid. Based on our results, all these plants had antioxidant and antiglycating activities, among them S. choloroleuca seems to be the most effective one. Furthermore, these species not only showed no cytotoxic effects in neuron-like PC12 cells, but also protected them against oxidative stress-induced cell death, exerted by H(2)O(2). We further showed that these plants increase superoxide dismutase and catalase levels, reduce lipid peroxidation and up regulate hemeoxygenase-1 and glutamylcysteine synthetase proteins. This study raised the possibility of developing these plants as potential neuroprotective agents.