Neurodegenerative polyglutamine (polyQ) expansion disorders such as Huntington’s disease (HD) are devastating, progressive and ultimately fatal diseases with no effective treatment or cure. The molecular hallmark of the diseases is an age-dependent, neurotoxic aggregation of polyglutamine-proteins. The fundamental cellular processes triggering this neurotoxic protein aggregation are poorly understood, resulting in a scarcity of drug targets for developing therapeutic strategies. Interestingly, glucose uptake into the brain is reduced in both HD patients and animal models. Reduced brain glucose metabolism precedes both motor symptoms and tissue loss, and the degree of glucose-hypometabolism appears to affect age of symptom-onset, with larger decreases in glucose uptake correlating with earlier disease onset. Recent studies in yeast and bacteria in have shown that the material properties of the cytosol in these cells change upon reduced glucose-uptake, leading the liquid-like cytosol to appear more solid-like, which in turn results in increased protein aggregation. We hypothesized that a similar response to reduced glucose-metabolism may change the material properties of the neuronal cytosol and thereby contribute to triggering the neurotoxic aggregation of polyQ-proteins in HD and other neurodegenerative polyglutamine expansion disorders.
The overall objectives of the project were to determine whether:
1. mammalian neurons regulate cytoplasmic diffusion and display a stress response that changes the material properties of the cytosol,
and whether
2. this neuronal stress response upon nutrient-starvation or ageing is sufficient to trigger aggregation of polyglutamine-proteins.
