A protein quality control (PQC) system exists within eukaryotic cells to facilitate the efficient degradation of misfolded proteins. Currently, the primary PQC activities are believed to be found in the endoplasmic reticulum (ER), ubiquitin-proteasome system (UPS) and lysosome[1–3]. Misfolded proteins can first be recognized immediately after translation in the ER, where heat shock proteins (HSPs) bind misfolded proteins and catalyze refolding. If refolding is unsuccessful, misfolded protein are then transported into the cytosol where they are targeted for degradation by the ubiquitin-proteasome system or by the lysosome.

The quantity and severity of misfolded proteins can overwhelm the capacity of the PQC system and may lead to protein aggregate accumulation. Misfolded proteins that can not be degraded tend to be more toxic to cells. Aggregated proteins can accumulate into an intracellular inclusion body termed aggresome which is considered a temporary protective mechanism to confine potentially toxic proteins. Dividing cells can relieve this toxicity by passing aggregated proteins onto daughter cells; however, in post-mitotic cells such as neurons this mechanism is not possible and may make these cells more susceptible to toxic protein aggregates. Therefore, disorders of protein folding and degradation are emerging as a fundamental mechanism in the pathogenesis of many diseases, especially neurodegenerative diseases.

The UPS system is essential for many cellular processes, including the cell cycle, the regulation of gene expression, and responses to oxidative stress. In the UPS, misfolded proteins are first covalently labeled with ubiquitin, a small conserved protein, through the process of ubiquitination or ubiquitinylation. This is an ATP-dependent process that involves the action of at least three enzymes that work in concert: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3) [2, 4]. Ubiquitinylation is an important regulatory tool that controls the concentration of key signaling proteins, such as those involved in cell cycle control, as well as removing misfolded, damaged or mutant proteins that could be harmful to the cell. Abnormal ubiquitinylation of proteins can result in intracellular accumulations, aggresomes. Examples of such inclusions bodies include neurofibrillary tangles (Alzheimer’s disease), Lewy body (Parkinson’s disease), Pick bodies (Pick’s disease) and Mallory’s Hyalin (alcoholic liver disease). After a polyubiquitinated chain is formed, the proteins will be delivered to the proteasome specifically for degradation (Figure 1).

Four genes have been confirmed to be involved in AD, including APP, PSEN1, PSEN2, and ApoE[6]. Several lines of experimental evidence support a role for Ubiquilin 1, and by extension PQC, in AD pathogenesis. First, at the genetic level, Bertram et al reported that a Ubiquilin 1 polymorphism substantially increase AD risk, possibly by influencing Ubiquilin 1 alternative splicing in the brain [7]. Second, at the neuropathological level, anti-Ubiquilin antibodies robustly stained neurofibrillary tangles and Lewy bodies in AD and PD affected brains, respectively. Third, functionally, Ubiquilin 1 regulates γ-secretase (the APP cleavage proteases which can produce Aβ) activity by regulating endoproteolysis of the presenilin 1 protein within the γ-secretase complex [8, 9]. In addition, a functional interaction between Ubiquilin 1 and presenilin 1 was detected in vitro as well as in brain tissue of healthy controls and AD patients. Massey et al reported Ubiquilin 1 and PS proteins co-localized in vesicular-like structure or ER- like pattern [8, 10]. Finally, Ubiquilin 1 affects APP trafficking and processing, thereby influencing the generation of Aβ. Taken together, these results strongly suggest that Ubiquilin 1 may be involved in AD pathogenesis.

Polyglutamine (PolyQ) diseases are a category of neurodegenerative diseases characterized by expanded PolyQ tracts. Based on clinical features PolyQ diseases are classified into nine different types, e.g. Huntington’s disease (HD) and spinocerebellar ataxia type1 (SCA1). Despite the variety of clinical symptoms they seem to share the same underlying mechanism, CAG trinucleotide repeat expansion within gene coding regions which results in abnormally large glutamine repeats. This expansion leads to aggregation of the affected protein which overwhelms the PQC system. Recent evidence suggested that Ubiquilin family proteins are involved in the pathophysiology of PolyQ diseases. SCA1 is a genetic disorder clinically characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Mutations in the gene encoding ataxin 1 (ATX1 or SCA1) cause the disease. The interaction between Ataxin 1 and Ubiquilin 4 (also known as ataxin-1-interacting protein, A1UP) may be involved with SCA1 pathogenesis. Huntingtin’s disease (HD) is another genetic disorder characterized by mutations in the Huntingtin (Htt) gene. Mutant Huntingtin proteins (mHtt) form nuclear inclusions and neuropil aggregates which results in neuronal cell death in select areas of the brain and is responsible for the abnormal body movements and lack of coordination observed in the disease. Wang and colleagues reported that Ubiquilin 1 suppresses polyQ-induced protein aggregation and toxicity in cells and in an animal model of HD.