Targeting expression of expanded polyglutamine proteins to the endoplasmic reticulum or mitochondria prevents their aggregation

Abstract

Aggregation of misfolded proteins is a characteristic of several neurodegenerative diseases. The huntingtin amino-terminal fragment with extended polyglutamine repeat forms aggregates closely associated with chaperones both in the cytoplasm and the nucleus. Because each cellular compartment contains distinct chaperones and because the molecular mechanisms controlling polyglutamine aggregation are largely unknown, we decided to investigate the influence of different cellular environments on the aggregation of this pathological protein. Here, we show that aggregation of a protein containing a polyglutamine stretch of pathological length is abolished when its expression is targeted to the endoplasmic reticulum. Once retrogradely transported outside the endoplasmic reticulum, the aggregation-prone polyglutaminecontaining protein recovers its ability to aggregate. When expressed in the mitochondria, a protein containing 73 glutamines is entirely soluble, whereas the nucleocytosolic equivalent has an extremely high tendency to aggregate. Our data imply that polyglutamine aggregation is a property restricted to the nucleocytosolic compartment and suggest the existence of compartmentspecific cofactors promoting or preventing aggregation of pathological proteins.

Misfolding of Proteins with a Polyglutamine Expansion Is Facilitated by Proteasomal Chaperones

“…In agreement with biophysical data, we found that in cells large amounts of Htt fragments with expanded poly(Q) can be expressed in a soluble state (this study and Ref. 55). This implies that aggregation is not just a consequence of an increase in concentration but is dependent in the cellular milieu on additional events.…”

Pathogenic and Non-pathogenic Polyglutamine Tracts Have Similar Structural Properties: Towards a Length-dependent Toxicity Gradient

“…Any factor that modulates the cellular environment, with respect to functions involved in protein homeostasis such as folding and degradation, should therefore influence the length at which polyQ becomes toxic. Along this line, Rousseau et al 30 showed that mutant huntingtin harbouring 73Q, while readily aggregating in the cytosolic compartment of 293T cells, remains soluble when addressed to the endoplasmic reticulum or mitochondria, suggesting the existence of pro or antiaggregation factors in different compartments.…”

Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins

“…Recently it was shown that the targeting of aminoterminal polyQ-containing huntingtin protein fragments to the ER reduces the amount of protein aggregates observed in transfected 293T fibroblasts [38]. This data suggests the existence of organelle-specific modulators that affect mutant protein aggregate formation and cell viability via the ER.…”