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Chemical genetic-mediated spatial regulation of protein expression in neurons reveals an axonal function for wld(s).

ABSTRACT: The degeneration of axons is the underlying pathological process of several neurological disorders. The Wallerian degeneration (Wld(S)) slow protein, which is primarily nuclear, markedly inhibits axonal degeneration. Contradictory models have been proposed to explain its mechanism, including a role in the nucleus, where it affects gene transcription, and roles outside the nucleus, where it regulates unknown effectors. To determine which pool of Wld(S) accounts for its axon-protective effects, we developed a strategy to control the spatial expression of proteins within neurons. This strategy couples a chemical genetic method to control protein stability with microfluidic culturing. Using neurons that are selectively deficient in Wld(S) in axons, we show that the axonal pool of Wld(S) is necessary for protection from axon degeneration. These results implicate an axonal pathway regulated by Wld(S) that controls axon degeneration.

SUBMITTER: Cohen MS

PROVIDER: S-EPMC3292772 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Chemical genetic-mediated spatial regulation of protein expression in neurons reveals an axonal function for wld(s).

Cohen Michael S MS Ghosh Ananda K AK Kim Hyung Joon HJ Jeon Noo Li NL Jaffrey Samie R SR

Chemistry & biology 20120201 2

The degeneration of axons is the underlying pathological process of several neurological disorders. The Wallerian degeneration (Wld(S)) slow protein, which is primarily nuclear, markedly inhibits axonal degeneration. Contradictory models have been proposed to explain its mechanism, including a role in the nucleus, where it affects gene transcription, and roles outside the nucleus, where it regulates unknown effectors. To determine which pool of Wld(S) accounts for its axon-protective effects, we ...[more]

PMID: 22365601

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Project description:Tauopathy is characterized by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule-associated protein tau. The neuronal changes evident in tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by co-expression of WldS. In a Drosophila model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, WldS was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit OR47b was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of WldS completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldS was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, WldS expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of WldS intersects with the mechanism(s) of degeneration initiated by tau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.

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Chemical genetic-mediated spatial regulation of protein expression in neurons reveals an axonal function for wld(s).

Publications

Chemical genetic-mediated spatial regulation of protein expression in neurons reveals an axonal function for wld(s).

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