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Identifying polyglutamine protein species in situ that best predict neurodegeneration.

ABSTRACT: Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.

SUBMITTER: Miller J

PROVIDER: S-EPMC3271120 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Identifying polyglutamine protein species in situ that best predict neurodegeneration.

Miller Jason J Arrasate Montserrat M Brooks Elizabeth E Libeu Clare Peters CP Legleiter Justin J Hatters Danny D Curtis Jessica J Cheung Kenneth K Krishnan Preethi P Mitra Siddhartha S Widjaja Kartika K Shaby Benjamin A BA Lotz Gregor P GP Newhouse Yvonne Y Mitchell Emily J EJ Osmand Alex A Gray Michelle M Thulasiramin Vanitha V Saudou Frédéric F Segal Mark M Yang X William XW Masliah Eliezer E Thompson Leslie M LM Muchowski Paul J PJ Weisgraber Karl H KH Finkbeiner Steven S

Nature chemical biology 20111030 12

Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of pol ...[more]

PMID: 22037470

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Project description:Chronic anal fissure (CAF) is a painful tear or crack which occurs in the anoderm. The optimal algorithm of therapy for CAF is still debated. Lateral internal sphincterotomy (LIS) is a surgical treatment, considered as the 'gold standard' therapy for CAF. It relieves CAF symptoms with a high rate of healing. Chemical sphincterotomy (CS) with nitrates, calcium blockers or botulinum toxin (BTX) is safe, with the rapid relief of pain, mild side-effects and no risk of surgery or anesthesia, but is a statistically less effective therapy for CAF than LIS. This article considers if aggressive treatment should only be offered to patients who fail pharmacological sphincterotomy. Aspects of anal fissure etiology, epidemiology and pathophysiology are considered with their meaning for further management of CAF. A molecular model of chemical interdependence significant for the chemistry of CAF healing is examined. Its application may influence the development of optimal therapy for CAF. BTX is currently considered the most effective type of CS and discussion in this article scrutinizes this method specifically. Although the effectiveness of BTX vs. LIS has been discussed, the essential focus of the article concerns identifying the best therapy application for anal fissure. Elements are presented which may help us to predict CAF healing. They provide rationale for the expansion of the CAF therapy algorithm. Ethical and economic factors are also considered in brief. As long as the patient is willing to accept the potential risk of fecal incontinence, we have grounds for the 'gold standard' (LIS) as the first-line treatment for CAF. The author concludes that, when the diagnosis of the anal fissure is established, CS should be considered for both ethical and economic reasons. He is convinced that a greater understanding and recognition of benign anal disorders by the GP and a proactive involvement at the point of initial diagnosis would facilitate the consideration of CS at an earlier, more practical stage with improved outcomes for the patient.

Dataset Information

Identifying polyglutamine protein species in situ that best predict neurodegeneration.

Publications

Identifying polyglutamine protein species in situ that best predict neurodegeneration.

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