Ubiquitin-proteasome system involvement in Huntington's disease

Abstract

Huntington's disease (HD) is a genetic autosomal dominant neurodegenerative disease caused by the expansion of a CAG repeat in the huntingtin (htt) gene. This triplet expansion encodes a polyglutamine stretch (polyQ) in the N-terminus of the high molecular weight (348-kDa) and ubiquitously expressed protein htt. Normal individuals have between 6 and 35 CAG triplets, while expansions longer than 40 repeats lead to HD. The onset and severity of the disease depend on the length of the polyQ tract: the longer the polyglutamine stretch (polyQ) is, the earlier the disease begins and the more severe the symptoms are. One of the main histopathological hallmarks of HD is the presence of intraneuronal proteinaceous inclusion bodies, whose prominent and invariant feature is the presence of ubiquitin (Ub); therefore, they can be detected with anti-ubiquitin and anti-proteasome antibodies. This, together with the observation that mutations in components of the ubiquitin-proteasome system (UPS) give rise to some neurodegenerative diseases, suggests that UPS impairment may be causative of HD. Even though the link between disrupted Ub homeostasis and protein aggregation to HD is undisputed, the functional significance of these correlations and their mechanistic implications remains unresolved. Moreover, there is no consistent evidence documenting an accompanying decrease in levels of free Ub or disruption of Ub pool dynamics in neurodegenerative disease or models thus suggesting that the Ub-conjugate accumulation may be benign and just underlie lesion in 26S function. In this chapter we will elaborate on the different studies that have been performed using different experimental approaches, in order to shed light to this matter.

Keywords: Huntington’s disease; animal models; degron-fluorescent proteins; inclusion body; ubiquitin–proteasome system.

FIGURE 1

Neurodegenerative diseases caused by CAG/polyQ expansion. HD, Huntington’s disease; SCA1, spinocerebellar ataxia 1; DRPLA, dentatorubral-pallidoluysian atrophy; SCA7, spinocerebellar ataxia 7; MJD, Machado–Joseph dystrophy; SCA2, spinocerebellar ataxia 2; SBMA, spinobulbar muscular atrophy; SCA17, spinocerebellar ataxia 17; SCA6, spinocerebellar ataxia 6. The lower underlined number in each pathology represent the pathological threshold of the disease, the last underlined number represents the longest repetition analyzed. ORF, open reading frame.

FIGURE 2

Protein targeting and degradation by the UPS. E1, E2, E3, and E4 enzymes are in charge for transferring the Ub molecules (pink circles) to the substrates (blue). This process requires energetic in term of ATP molecules. The proteasome is the protease responsible for the proteolysis of the substrates into small peptides. The polyubiquitin chain is not degraded by the proteasome, DUBs enzymes separate them from the substrate and divide them into monomers ready to be reused.