Editors' ChoiceNeuroscience

FATtening Up Against Neurodegeneration

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Sci. Signal.  08 Mar 2011:
Vol. 4, Issue 163, pp. ec67
DOI: 10.1126/scisignal.4163ec67

Expansion of a CAG trinucleotide in the atrophin-1 (at-1) gene results in the insertion of stretches of polyglutamine (polyQ) residues in the AT-1 protein (which is a transcription factor) and a cerebellar ataxia syndrome in humans called dentatorubral-pallidoluysian atrophy (DRPLA). Napoletano et al. performed genome-wide transcriptional profiling of Drosophila expressing polyQ Atrophin (Atro) in photoreceptors. Transcription of the fat (ft) gene was decreased in polyQ Atro flies, and Atro bound to an enhancer region upstream of the ft promoter. Fat is an atypical cadherin that participates in the Hippo signaling pathway, which controls organ size by regulating proliferation and apoptosis. Photoreceptor loss in polyQ Atro flies was increased with expression of loss-of-function alleles of ft. Flies expressing mutant ft as well as mutant versions of other components of the Hippo pathway—warts (wts), salvador (sav), and hippo (hpo)—also showed progressive neuronal photoreceptor degeneration, suggesting the involvement of the Hippo pathway in neurodegeneration. ft mutant photoreceptors showed increased numbers of autophagosomes with age and increased amounts of p62 (a protein that is degraded by autophagy), suggesting that defects in the Hippo pathway cause neurodegeneration through impaired autophagy. Thus, the neurodegeneration seen in DRPLA could be due to inhibition of Hippo signaling and therefore impaired autophagy by polyQ Atro.

F. Napoletano, S. Occhi, P. Calamita, V. Volpi, E. Blanc, B. Charroux, J. Royet, M. Fanto, Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat. EMBO J. 30, 945–958 (2011). [PubMed]