Vagrant Molecule

This article and its accompanying poster illustrate how impaired RNA metabolism can underlie the pathophysiology of neurodegeneration, as well as discussing potential therapeutic interventions to target these processes.The ALS research community is now poised to translate these findings to the clinic.A related DMM review published in highlighted the impact that zebrafish models in particular have made in improving our understanding of the pathogenic mechanisms underpinning ALS and related motor neuron disorders. Some focus on modeling human gene defects in animals, whereas others develop biomarkers to track disease progression.In each case, they show how diverse model systems can be powerfully used to explore the mechanisms of neurodegeneration.Below, we highlight the key findings and translational implications of a subset of the new research papers published in this issue.Dogs can develop a type of neurodegenerative disorder called degenerative myelopathy, which can be caused by mutations in the same gene that is frequently mutated in human ALS: superoxide dismutase expression is upregulated in human ALS and in a mouse model of ALS caused by SOD mutations led the authors to test for similar effects in the dog model.Consistent with previous results, they found that CB receptor expression is upregulated in the spinal cord of dogs affected by degenerative myelopathy. These results lend weight to the putative neuroprotective effect of CB receptor modulation in ALS, and further support the use of canine degenerative myelopathy as a relevant model to study the pathophysiology of this disease.The dog model represents the first spontaneous animal model of ALS, offering several advantages over models that rely on transgenic overexpression.The new conditional mouse model generated here can be used for further mechanistic exploration. Loss of appetite and weight loss are common features of neurodegenerative diseases such as ALS.In addition to shedding light on the neuropathological basis of anorexia, their findings could help suggest strategies to prevent or slow weight loss that accompanies neurodegenerative disorders.The neuromuscular junction is a remarkable structure that is particularly vulnerable to neurodegenerative disease.However, it possesses powerful ways to resist injury and to regenerate.A group of disorders called hereditary sensory and autonomic neuropathies are caused by PNS dysfunction.One such disorder, familial dysautonomia, is caused by mutation of the IKBKAP gene.The mutant mice develop both autonomic and nonautonomic neuronal deficits, suggesting a role for IKBKAP beyond the PNS, to CNS development and function.Parkinsons disease is one of the most common agerelated neurodegenerative disorders worldwide.The ability to predict and detect the disease presymptomatically on the basis of biomarkers is likely to give therapies the best chance of working.Noninvasive biomarkers, such as blood or imagingbased markers are ideal, because they can be analyzed longitudinally and could even be used to track the efficacy of a proposed treatment.Their study provides a new blood biomarker with the potential to be used in early screens for PD risk.Defining intrinsic cellular defects that characterize a particular disease state can provide mechanistic insight but could also serve as a biomarker to predict disease based on analysis of patient cells.These findings reinforce a role for autophagy dysregulation in ALS and also provide a potential cellular biomarker of the disease.

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