Abstract
In polyglutamine diseases, an abnormally elongated polyglutamine results in protein misfolding and accumulation of intracellular aggregates. Autophagy is a major cellular degradative pathway responsible for eliminating unnecessary proteins, including polyglutamine aggregates. Basal autophagy constitutively occurs at low levels in cells for the performance of homeostatic function, but the regulatory mechanism for basal autophagy remains elusive. Here we show that the Na+/H+ exchanger (NHE) family of ion transporters affect autophagy in a neuron-like cell line (Neuro-2a cells). We showed that expression of NHE1 and NHE5 is correlated to polyglutamine accumulation levels in a cellular model of Huntington's disease, a fatal neurodegenerative disorder characterized by accumulation of polyglutamine-containing aggregate formation in the brain. Furthermore, we showed that loss of NHE5 results in increased polyglutamine accumulation in an animal model of Huntington's disease. Our data suggest that cellular pH regulation by NHE1 and NHE5 plays a role in regulating basal autophagy and thereby promotes autophagy-mediated degradation of proteins including polyglutamine aggregates.
Highlights
Accumulation and aggregation of mutant proteins is a characteristic feature of a number of neurodegenerative disorders, including Parkinson’s disease and Huntington’s disease (HD) [1]
Among physiologically relevant neuronal environmental changes that affect intracellular protein degradation, we chose to examine the effect of environmental pH changes on neuronal autophagy, because lysosomal protein degradation is heavily dependent on cellular pH regulation [16]
We found that numbers of EGFP-positive spots were significantly increased by incubating the cells under normal air, while EGFP spot formation was not significantly affected by serum deprivation using DMEM lacking serum as culture media (FBS(2)) or by serum/amino aciddeprivation using Krebs-Ringer bicarbonate solution (KRB)(Fig. 2A)
Summary
Accumulation and aggregation of mutant proteins is a characteristic feature of a number of neurodegenerative disorders, including Parkinson’s disease and Huntington’s disease (HD) [1]. In HD, for example, the disease-causing mutation in huntingtin (HTT), a protein of uncertain function causes expansion of a stretch of glutamines (polyQ) near its N terminus, and the mutant form of HTT accumulates as nuclear and cytoplasmic inclusions in an HD brain [2]. Autophagy is a cellular protein clearance mechanism and can, in principle, clear aggregation-prone proteins [3]. In this process, double-membrane organelles, called autophagosomes, engulf cellular proteins and organelles and fuse with lysosomes to form autolysosomes, which degrade the organelle’s contents [3]. Some previous reports showed that mutated HTT expression may be associated with up-regulated autophagy, and autophagy degrades polyQ-expanded proteins [4,5]
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