Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder. Recent systematic meta-analysis results suggest that AD risk is modulated by numerous genes, each displaying a small yet significant effect on risk[5
]. Approximately 70% of the genetic variance of AD has yet to be determined. Considerable genetic, biochemical, and molecular biological evidence suggests that the excessive accumulation of a small peptide, Aβ, is the primary pathological event leading to AD[6
]. Aβ is produced through a sequential cleavage pathway of β-amyloid precursor protein (APP). Proteins that alter APP cleavage activities have been considered good AD therapeutic targets.
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
]. 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
]. 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.
Cancer is characterized by uncontrolled cell division Cyclins and cyclin-dependent kinases (CDKs) are the two critical classes of molecules in regulation of cell cycle progression. Funakoshi and colleagues reported that Xenopus orthologues of Ubiquilin 1, XDRP1, binds cyclin A (A1 and A2) and arrested embryonic Xenopus cell division. Ubiquilin 1 has also been reported to interact with the tumor-suppressor proteins DAN and S (1–5), which modulates DNA synthesis and therefore cell division. Finally, in lung adenocarcinoma samples Ubiquilin 1 mRNA and protein levels are both significantly increased. Interestingly, the phosphorylated form of the Ubiquilin 1 protein is significantly reduced in these same samples. Taken together, there is strong evidence that Ubiquilin 1 is involved in pathogenesis of a number of diseases.