Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein

Abstract

Aggregation of disease proteins is believed to be a central event in the pathology of polyglutamine diseases, whereas the relationship between aggregation and neuronal death remains controversial. We investigated this question by expressing mutant huntingtin (htt) with a defective adenovirus in different types of neurons prepared from rat cerebral cortex, striatum or cerebellum. The distribution pattern of inclusions is not identical among different types of primary neurons. On day 2 after infection, cytoplasmic inclusions are dominant in cortical and striatal neurons, whereas at day 4 the ratio of nuclear inclusions overtakes that of cytoplasmic inclusions. Meanwhile, nuclear inclusions are always predominantly present in cerebellar neurons. The percentage of inclusion-positive cells is highest in cerebellar neurons, whereas mutant htt induces cell death most remarkably in cortical neurons. As our system uses htt exon 1 protein and thus aggregation occurs independently from cleavage of the full-length htt, our observations indicate that the aggregation process is distinct among different neurons. Most of the neurons containing intracellular (either nuclear or cytoplasmic) aggregates are viable. Our findings suggest that the process of mutant htt aggregation rather than the resulting inclusion body is critical for neuronal cell death.

Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease

“…Although several studies have found aggregates to be associated with cell death, [8][9][10] others have found no correlation between aggregation of mutant htt and cellular toxicity. 11,12,13 A provocative study has found that the presence of inclusion bodies containing mutant htt may actually predict lower risk of cell death in primary neurons. 14 Indeed, it has been DZNE, German Center for Neurodegenerative Diseases, suggested that htt aggregates may represent a molecular sink for soluble toxic htt forms.…”

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

“…Several studies have suggested that not all forms of aggregates may be toxic [70][71][72]. In fact, large (amyloidic) aggregates that entrap these various key cellular elements have been found to be protective in certain systems and under certain conditions [70][71][72][73][74][75]. It has thus been proposed that smaller (amorphic) oligomeric and/or heteromeric species are more toxic as they are capable of freely moving around in the cellular milieu and perturb various neuronal functions.…”

Huntingtin Aggregation Kinetics and Their Pathological Role in aDrosophilaHuntington’s Disease Model

“…Many classic HD models express exon 1 of the mutant protein Jackson et al 1998;Krobitsch and Lindquist 2000;Tagawa et al 2004), which is capable of forming inclusions postulated to play a role in HD pathology Becher et al 1998). To determine whether the in vivo subcellular localization of the 81-aa exon 1 fragment of pathogenic human Htt (HttQ96-GFP) differs from that of the 588-aa pathogenic Htt fragment in our Drosophila model, HttQ96-GFP-expressing third instar larvae were imaged using confocal microscopy.…”