Kervin, K. | Search bioRxiv

bioRxiv2021

Dietary vitamin B12 reduces amyloid-β proteotoxicity by alleviating oxidative stress and mitochondrial dysfunction

Alzheimers disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, complexity of the human diet and indirect effects of the microbiome make it challenging to identify protective nutrients. Multiple factors contribute to AD pathogenesis including amyloid beta (A{beta}) deposition, mitochondrial dysfunction, and oxidative stress. Here we used Caenorhabditis elegans to define the impact of diet on A{beta} proteotoxicity. We discovered that dietary vitamin B12 alleviated mitochondrial fragmentation, bioenergetic defects, and oxidative stress, delaying A{beta}-induced paralysis without affecting A{beta} accumulation. Vitamin B12 had this protective effect by acting as a cofactor for methionine synthase rather than as an antioxidant. Vitamin supplementation of B12 deficient adult A{beta} animals was beneficial, demonstrating potential for vitamin B12 as a therapy to target pathogenic features of AD triggered by both aging and proteotoxic stress.

cell biology↗

bioRxiv2020

A C. elegans genome-wide RNAi screen for altered levamisole sensitivity identifies genes required for muscle function

At the neuromuscular junction (NMJ), postsynaptic ionotropic acetylcholine receptors (AChRs) transduce a chemical signal released from a cholinergic motor neuron into an electrical signal to induce muscle contraction. To identify regulators of postsynaptic function, we conducted a genome-wide RNAi screen for genes required for proper response to levamisole, a pharmacological agonist of ionotropic L-AChRs at the Caenorhabditis elegans NMJ. A total of 117 gene knockdowns were found to cause levamisole hypersensitivity, while 18 resulted in levamisole resistance. Our screen identified conserved genes important for muscle function including some that are mutated in congenital myasthenic syndrome, congenital muscular dystrophy, congenital myopathy, myotonic dystrophy, and mitochondrial myopathy. Of the genes found in the screen, we further investigated those predicted to play a role in endocytosis of cell surface receptors. Loss of the Epsin homolog epn-1 had opposing effects on the levels of postsynaptic L-AChRs and GABAA receptors, resulting in increased and decreased abundance, respectively. This disrupts the balance of postsynaptic excitatory and inhibitory signaling, causing levamisole hypersensitivity. We also examined other genes that resulted in a levamisole hypersensitive phenotype when knocked down including gas-1, which functions in Complex I of the mitochondrial electron transport chain. Consistent with altered ATP synthesis impacting levamisole response, treatment of wild-type animals with levamisole resulted in L-AChR dependent depletion of ATP levels. These results suggest that the paralytic effects of levamisole ultimately lead to metabolic exhaustion.

genetics↗