Proteolytic Cleavage of Polyglutamine Disease-Causing Proteins: Revisiting the Toxic Fragment Hypothesis

Abstract

Proteolytic cleavage has been implicated in the pathogenesis of diverse neurodegenerative diseases involving abnormal protein accumulation. Polyglutamine diseases are a group of nine hereditary disorders caused by an abnormal expansion of repeated glutamine tracts contained in otherwise unrelated proteins. When expanded, these proteins display toxic properties and are prone to aggregate, but the mechanisms responsible for the selective neurodegeneration observed in polyglutamine disease patients are still poorly understood. It has been suggested that the neuronal toxicity of polyglutamine-expanded proteins is associated with the production of deleterious protein fragments. This review aims at discussing the involvement of proteolytic cleavage in the six types of spinocerebellar ataxia caused by polyglutamine expansion of proteins. The analysis takes into detailed consideration evidence concerning fragment detection and the mechanisms of fragment toxicity. Current evidence suggests that the proteins involved in spinocerebellar ataxia types 3, 6 and 7 give rise to stable proteolytic fragments. Fragments carrying polyglutamine expansions display increased tendency to aggregate and toxicity, comparing with their non-expanded counterparts or with the correspondent full-length expanded proteins. Data concerning spinocerebellar ataxia types 1, 2 and 17 is still scarce, but available results afford further investigation. Available literature suggests that proteolytic cleavage of expanded polyglutamine-containing proteins enhances toxicity in disease-associated contexts and may constitute an important step in the pathogenic cascade of polyglutamine diseases. Countering protein fragmentation thus presents itself as a promising therapeutic aim.

PolyQ‐expanded huntingtin and ataxin‐3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin

“…We also performed an imaging experiment to visualize colocalization of UBQLN2 with the inclusions. The inclusions formed by Htt 100Q ‐N90 are more and larger than those by Htt 100Q ‐N552, consistent with the finding that the shorter polyQ fragments are more prone to aggregation and more toxic (52, 53). The images showed that UBQLN2 colocalized with the inclusions of Htt 100Q ‐N90, and some formed puncta around the inclusions (Supplemental Fig.…”

Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch

“…Fragmented polyQ proteins have been found in patients and proteolytic processing of polyQ proteins into smaller, highly aggregation-prone fragments that are more toxic than the full-length protein has been described for most polyQ diseases, HD (Mangiarini et al, 1996; Martindale et al, 1998), DRPLA (Igarashi et al, 1998; Wellington et al, 1998), SBMA (Butler et al, 1998; Kobayashi et al, 1998; Wellington et al, 1998), and SCAs (Ikeda et al, 1996; Paulson et al, 1997; Zander et al, 2001; Goti et al, 2004; Helmlinger et al, 2004; Kordasiewicz et al, 2006; Matos et al, 2016a; Figure 2B). However, for SCA1, SCA2, and SCA17 the evidence for the presence of fragments is limited (Matos et al, 2016a).…”

“…However, for SCA1, SCA2, and SCA17 the evidence for the presence of fragments is limited (Matos et al, 2016a). Proteases play a key role in the generation of these polyQ fragments, and inhibition of proteases or mutation of their cleavage sites can modulate the disease AO (Ona et al, 1999; Chen et al, 2000; Graham et al, 2006; Aharony et al, 2015).…”

“…Importantly, expression of these fragments containing the polyQ stretch can already give rise to aggregation and the disease phenotype (Ikeda et al, 1996), although it is still not entirely clear why the polyQ fragments display enhanced toxicity when compared to their respective full-length proteins. Cleavage may lead to changes in aggregation propensity, conformation of the protein, localization, and molecular interactions (Matos et al, 2016a). For SBMA, it has been reported that a conformational change exposing the polyQ tract is already sufficient to drive aggregation (Heine et al, 2015) and cleavage might expose the polyQ stretch in a similar way as such a conformational change does.…”

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

“…This suggests a possible impairment in the UPS which, if perpetuated, might result in toxicity and neurodegeneration. The malfunction of the UPS can also result in increased cleavage of mutant proteins into smaller, more toxic fragments, which have been implicated in the pathogenesis of diverse neurodegenerative traits involving abnormal protein accumulation (Li et al, 2010; Matos et al, 2017). In SCA2, the artificial inhibition of the UPS originated a 70 KDa fragment in cells transfected with mutant ataxin-2, but not in those transfected with the WT form.…”