(31) ​​Expression of a human polyglutamine protein in Caenorhabditis elegans neurons disrupts the heat shock response

     Expansions of polyglutamine (polyQ) tracts in different proteins account for nine neurodegenerative diseases including Machado Joseph disease (MJD). MJD is a dominantly inherited progressive ataxia that is caused by a... [ view full abstract ]

     Expansions of polyglutamine (polyQ) tracts in different proteins account for nine neurodegenerative diseases including Machado Joseph disease (MJD). MJD is a dominantly inherited progressive ataxia that is caused by a polyQ tract embedded within the C-terminal domain of the ataxin-3 (AT3) protein. The polyQ expansion disrupts the thermodynamics of protein folding, causing AT3 to aggregate and become neurotoxic. This aggregation and toxicity was previously modeled in C. elegans by expressing a disease-associated fragment of the human AT3 protein (cAT3) under the control of a pan-neuronal promoter. We show that expression of this protein fragment in neurons disrupts the organismal heat shock response (HSR) in a polyQ length-dependent manner. The data corroborate findings that C. elegans neurons control the HSR of the animal and demonstrate that the polyQ-containing cAT3 protein fragment is sufficiently toxic to interfere with this neuronal function.