Impaired ERAD and ER stress

HD Lighthouse Contributing Editor's Comment: Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity

This recent study sheds some light on the special vulnerability of striatal neurons to HD stress and suggests novel targets for potential HD therapies.

HD model cells conditional for production of a toxic fragment of the huntingtin HD+ protein were employed. These cells can be switched by nutrient manipulation from a state where the fragment is not produced to one where it is produced in abundance, allowing the time sequence of resulting pathologies to be observed.

Surprisingly, the earliest pathology observed was a build up of mis-folded proteins in the endoplasmic reticulum (ER), a system of vesicles in the cell where membrane proteins and proteins destined for secretion from the cell are manufactured. It is surprising because the huntingtin fragment is produced in the cytoplasm and forms its aggregates in the cytoplasm or nucleus and not in the ER. Nor does the HD fragment itself ever appear within the ER.

The authors showed that the toxic huntingtin fragment was combining with three proteins involved in the process that normally clears mis-folded proteins from the ER making them unavailable to perform this function. Over-production of these three proteins by genetic means prevented the toxicity.

Much of the work made use of the concept of ‘synthetic toxicity’, where two substances or genetic conditions whose toxicity is additive are thereby inferred to operate on the same mechanism. For instance, the authors observed that thapsigargin, an antibiotic that inhibits mis-folded protein clearance from the ER, was especially toxic to HD+ striatal neurons, suggesting that the ER was already stressed by the HD+ huntingtin protein.

Relieving the ER stress on striatal neurons could then be therapeutic for HD. Perhaps there is an anti-thapsigargin pro-biotic somewhere out there awaiting discovery.

An interesting aside of the work was the observation that the toxic fragment, the poly-glutamine end of the huntingtin protein, was no longer toxic when extended to include the adjacent poly-proline region of the molecule. In other studies covered previously in the Lighthouse [http://hdlighthouse.org/research/drugs-supps/updates/1266caspase6.php], caspase-6, whose suppression prevents HD pathology, was thought perhaps to cleave huntingtin between these two regions to create a similar toxic fragment.

-- Ron Mignery, Ph.D.
Posted to the HDL: 01-31-2009

Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity

Martin L. Duennwald and Susan Lindquist

abstract

Protein misfolding, whether caused by aging, environmental factors, or genetic mutations, is a common basis for neurodegenerative diseases. The misfolding of proteins with abnormally long polyglutamine (polyQ) expansions causes several neurodegenerative disorders, such as Huntington’s disease (HD). Although many cellular pathways have been documented to be impaired in HD, the primary triggers of polyQ toxicity remain elusive. We report that yeast cells and neuron-like PC12 cells expressing polyQ-expanded huntingtin (htt) fragments display a surprisingly specific, immediate, and drastic defect in endoplasmic reticulum (ER)-associated degradation (ERAD). We further decipher the mechanistic basis for this defect in ERAD: the entrapment of the essential ERAD proteins Npl4, Ufd1, and p97 by polyQ-expanded htt fragments. In both yeast and mammalian neuron-like cells, overexpression of Npl4 and Ufd1 ameliorates polyQ toxicity. Our results establish that impaired ER protein homeostasis is a broad and highly conserved contributor to polyQ toxicity in yeast, in PC12 cells, and, importantly, in striatal cells expressing full-length polyQ-expanded huntingtin.

Source: Genes and Development 2008 Dec 1;22(23):3308-19.