Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and noncell-autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV-gfaABC1 D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of the most vulnerable fast-fatigable MN until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast-twitch type IIB muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/reinnervation events. The transcriptome profiling of spinal cord MN shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes protects fast-fatigable motor units and thereby improves neuromuscular function in ALS mice.

The Links between ALS and NF-κB.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease wherein motor neuron degeneration leads to muscle weakness, progressive paralysis, and death within 3-5 years of diagnosis. Currently, the cause of ALS is unknown but, as with several neurodegenerative diseases, the potential role of neuroinflammation has become an increasingly popular hypothesis in ALS research. Indeed, upregulation of neuroinflammatory factors have been observed in both ALS patients and animal models. One such factor is the inflammatory inducer NF-κB. Besides its connection to inflammation, NF-κB activity can be linked to several genes associated to familial forms of ALS, and many of the environmental risk factors of the disease stimulate NF-κB activation. Collectively, this has led many to hypothesize that NF-κB proteins may play a role in ALS pathogenesis. In this review, we discuss the genetic and environmental connections between NF-κB and ALS, as well as how this pathway may affect different CNS cell types, and finally how this may lead to motor neuron degeneration.

Anti-Aß antibodies bound to neuritic plaques enhance microglia activity and mitigate tau pathology.

The brain pathology of Alzheimer's disease (AD) is characterized by the misfolding and aggregation of both the amyloid beta (Aß) peptide and hyperphosphorylated forms of the tau protein. Initial Aß deposition is considered to trigger a sequence of deleterious events contributing to tau pathology, neuroinflammation and ultimately causing the loss of synapses and neurons. To assess the effect of anti-Aß immunization in this context, we generated a mouse model by overexpressing the human tau protein in the hippocampus of 5xFAD mice. Aß plaque deposition combined with human tau overexpression leads to an array of pathological manifestations including the formation of tau-positive dystrophic neurites and accumulation of hyperphosphorylated tau at the level of neuritic plaques. Remarkably, the presence of human tau reduces microglial clustering in proximity to the Aß plaques, which may affect the barrier role of microglia. In this mouse model, continuous administration of anti-Aß antibodies enhances the clustering of microglial cells even in the presence of tau. Anti-Aß immunization increases plaque compaction, reduces the spread of tau in the hippocampal formation and prevents the formation of tau-positive dystrophic neurites. However, the treatment does not significantly reduce tau-induced neurodegeneration in the dentate gyrus. These results highlight that anti-Aß immunization is able to enhance microglial activity around neuritic plaques, mitigating part of the tau-induced pathological manifestations.

Author Correction: The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation.

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Oxidative Challenges of Avian Migration: A Comparative Field Study on a Partial Migrant.

Most avian migrants alternate flight bouts, characterized by high metabolic rates, with stopovers, periods of fuel replenishment through hyperphagia. High-energy metabolism and excessive calorie intake shift the balance between damaging prooxidants and antioxidants toward the former. Hence, migration likely affects the oxidative balance of birds. Migratory flight indeed appears to cause oxidative damage; however, whether migration affects the oxidative state of birds at stopover is unclear. Therefore, we compared total nonenzymatic antioxidant capacity (AOX) and malondialdehyde concentration (MDA; a measure of lipid peroxidation) in the plasma of migrant and resident common blackbirds. We also determined plasmatic uric acid (UA) and fatty acid (FA) concentrations and calculated a FA peroxidation index. Birds were sampled during autumn migration at a stopover site that also supports a sedentary blackbird population. Migrants had higher AOX than residents, also after correcting for UA concentration. Migrants tended to have higher FA peroxidation indexes than residents, indicating that the energy source of migrants contains higher concentrations of peroxidizable FAs. However, the two groups did not differ in MDA concentration, also not after correcting for peroxidation index. Peroxidation-corrected MDA concentration was negatively correlated with UA-corrected AOX. In other words, individuals with low nonenzymatic AOX suffered more from lipid peroxidation than individuals with high nonenzymatic AOX. These results together indicate that migrant blackbirds invest in antioxidant defenses to reduce oxidative damage to lipids, likely representing an adaptation to diminish the physiological costs of migration.

The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation.

A major hallmark of Parkinson's disease (PD) is the presence of Lewy bodies (LBs) in certain neuronal tissues. LBs are protein-rich inclusions, in which α-synuclein (α-syn) is the most abundant protein. Since these inclusions are not present in healthy individuals, despite the high concentration of α-syn in neurons, it is important to investigate whether natural control mechanisms are present to efficiently suppress α-syn aggregation. Here, we demonstrate that a CRISPR/Cas9-mediated knockout (KO) of a DnaJ protein, DNAJB6, in HEK293T cells expressing α-syn, causes a massive increase in α-syn aggregation. Upon DNAJB6 re-introduction into these DNAJB6-KO HEK293T-α-syn cells, aggregation is reduced to the level of the parental cells. We then show that the suppression of α-syn aggregation is dependent on the J-domain of DNAJB6, as the catalytically inactive protein, which carries the H31Q mutation, does not suppress aggregation, when re-introduced into DNAJB6-KO cells. We further demonstrate, that the suppression of α-syn aggregation is dependent on the molecular chaperone Hsp70, which is consistent with the well-known function of J-domains of transferring unfolded and misfolded proteins to Hsp70. These data identify a natural control strategy to suppress α-syn aggregation and suggest potential therapeutic approaches to prevent or treat PD and related disorders.