Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I

Walus, Mariusz; Kida, E; Golabek, Adam A.

doi:10.1002/humu.21251

Cited by 17 publications

(20 citation statements)

References 52 publications

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“…The pathology of ubiquitin-mediated turnover of missense variants of Msh2 is in keeping with mounting evidence that other human diseases, such as cystic fibrosis and Huntington, Alzheimer's, and Parkinson diseases are linked to proteinfolding abnormalities resulting in instability and ubiquitin-positive aggregates (18,19). Interestingly, diseases including neurofibromatosis (20), multiple endocrine neoplasia Type 1 (21), α-1 antitrypsin deficiency (22), classic late-infantile neuronal ceroid lipofuscinosis (23), and phenylketonuria (24) all have incidences in which missense variants are targeted by the ubiquitin-proteasome pathway. Thus, small-molecule stabilization of missense variants or the targeted inhibition of the ubiquitin pathway represent exciting avenues for therapeutic exploration for many diseases, not just Lynch syndrome.…”

Section: Other Clinically Significant Missense Variants May Also Be Rsupporting

confidence: 55%

Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2

Arlow

Scott

Wagenseller

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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MSH2 is required for DNA mismatch repair recognition in eukaryotes. Deleterious mutations in human MSH2 account for approximately half of the alleles associated with a common hereditary cancer syndrome. Previously, we characterized clinically identified MSH2 missense mutations, using yeast as a model system, and found that the most common cause of defective DNA mismatch repair was low levels of the variant Msh2 proteins. Here, we show that increased protein turnover is responsible for the reduced cellular levels. Increasing gene dosage of more than half of the missense alleles fully restored function. A titration experiment revealed that raising the expression level of one variant to less than wildtype levels restored mismatch repair, suggesting that overexpression is not always required to regain function. We found that the ubiquitin-mediated proteasome degradation pathway is the major mechanism for increased turnover of the Msh2 variants and identified the primary ubiquitin ligase as San1. Deletion of San1 restored protein levels for all but one variant, but did not elevate wild-type Msh2 levels. The unstable variants interacted with San1, whereas wild-type Msh2 did not. Additionally, san1Δ suppressed the mismatch repair defect of unstable variants. Of medical significance, the clinically approved drug Bortezomib partially restored protein levels and mismatch repair function for low-level variants and reversed the resistance to cisplatin, a common chemotherapeutic. Our results provide the foundation for an innovative therapeutic regime for certain mismatch-repair-defective cancers that are refractory to conventional chemotherapies.Lynch syndrome | MutS | mutator | hereditary nonpolyposis clorectal cancer L ynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a leading cause of inherited cancer mortality in the United States (1). Approximately 2-7% of colorectal cancer cases are the consequence of Lynch syndrome, a dominant and highly penetrant disease afflicting individuals at an early age (1). Although colorectal is the most common form of cancer found in Lynch syndrome families, endometrial, ovarian, stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate cancers are all associated with the syndrome.Lynch syndrome cancers, as well as many sporadic tumors, are a consequence of defects in mismatch repair; for example, ∼17% of all colorectal cancers originate from defects in mismatch repair (2). DNA mismatch repair is a conserved mechanism that significantly contributes to the accurate preservation of genetic material (3). Mismatch recognition is accomplished in eukaryotes by MutS heterodimers in which Msh2 is the invariant partner (4). Mismatch binding initiates subsequent events, including cleavage and excision of the error-containing strand followed by new synthesis and ligation (5). Without mismatch repair, DNA displays microsatellite instability and acquires numerous mutations, some of which are deleterious. Included among the types of harmfu...

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Section: Other Clinically Significant Missense Variants May Also Be Rsupporting

confidence: 55%

Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2

Arlow

Scott

Wagenseller

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…; Bellettato and Scarpa ; Walus et al . ). Although enzyme replacement therapy and gene therapy clinical trials are ongoing, no established drug‐mediated therapy is currently available for LINCL.…”

Section: Discussionmentioning

confidence: 97%

Gemfibrozil, food and drug administration‐approved lipid‐lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis

Ghosh

Rangasamy

Modi

et al. 2017

Journal of Neurochemistry

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Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) is a rare neurodegenerative disease caused by mutations in the Cln2 gene that leads to deficiency or loss of function of the tripeptidyl peptidase 1 (TPP1) enzyme. TPP1 deficiency is known to cause the accumulation of autofluoroscent lipid-protein pigments in brain. Similar to other neurodegenerative disorders, LINCL is also associated with neuroinflammation and neuronal damage. Despite investigations, no effective therapy is currently available for LINCL. Therefore, we administered gemfibrozil (gem), an FDA-approved lipid-lowering drug, which has been shown to stimulate lysosomal biogenesis and induce anti-inflammation, orally, at a dose of 7.5 mg/kg body wt/day to Cln2 (−/−) mice. We observed that gem-fed Cln2 (−/−) mice lived longer by more than 10 weeks and had better motor activity compared to vehicle (0.1% Methyl cellulose) treatment. Gem treatment lowered the burden of storage materials, increased anti-inflammatory factors like SOCS3 and IL-1Ra, upregulated anti-apoptotic molecule like phospho-Bad, and reduced neuronal apoptosis in the brain of Cln2 (−/−) mice. Collectively, this study reinforces a neuroprotective role of gem that may be of therapeutic interest in improving the quality of life in LINCL patients.

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“…Several genetic diseases corresponding to missense variants that are targeted by the ubiquitin-proteasome pathway, including cystic fibrosis, congenital erythropoietic porphyria, neurofibromatosis, Lynch syndrome, classic late-infantile neuronal ceroid lipofuscinosis, multiple endocrine neoplasia type 1, ␣-1 antitrypsin deficiency, and phenylketonuria, have been described previously (38)(39)(40)(41)(42)(43)(44). In several of the described cases, the destabilized mutant protein may nevertheless retain substantial functional properties.…”

Section: Discussionmentioning

confidence: 99%

129-Derived Mouse Strains Express an Unstable but Catalytically Active DNA Polymerase Iota Variant

Aoufouchi

Smet

Delbos

et al. 2015

Molecular and Cellular Biology

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cMice derived from the 129 strain have a nonsense codon mutation in exon 2 of the polymerase iota (Pol) gene and are therefore considered Pol deficient. When we amplified Pol mRNA from 129/SvJ or 129/Ola testes, only a small fraction of the full-length cDNA contained the nonsense mutation; the major fraction corresponded to a variant Pol isoform lacking exon 2. Pol mRNA lacking exon 2 contains an open reading frame, and the corresponding protein was detected using a polyclonal antibody raised against the C terminus of the murine Pol protein. The identity of the corresponding protein was further confirmed by mass spectrometry. Although the variant protein was expressed at only 5 to 10% of the level of wild-type Pol, it retained de novo DNA synthesis activity, the capacity to form replication foci following UV irradiation, and the ability to rescue UV light sensitivity in Pol ؊/؊ embryonic fibroblasts derived from a new, fully deficient Pol knockout (KO) mouse line. Furthermore, in vivo treatment of 129-derived male mice with Velcade, a drug that inhibits proteasome function, stabilized and restored a substantial amount of the variant Pol in these animals, indicating that its turnover is controlled by the proteasome. An analysis of two xeroderma pigmentosum-variant (XPV) cases corresponding to missense mutants of Pol, a related translesion synthesis (TLS) polymerase in the same family, similarly showed a destabilization of the catalytically active mutant protein by the proteasome. Collectively, these data challenge the prevailing hypothesis that 129-derived strains of mice are completely deficient in Pol activity. The data also document, both for 129-derived mouse strains and for some XPV patients, new cases of genetic defects corresponding to the destabilization of an otherwise functional protein, the phenotype of which is reversible by proteasome inhibition.

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Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I

Cited by 17 publications

References 52 publications

Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2

Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2

Gemfibrozil, food and drug administration‐approved lipid‐lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis

129-Derived Mouse Strains Express an Unstable but Catalytically Active DNA Polymerase Iota Variant

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