A functional variant of SHARPIN confers increased risk of late-onset Alzheimer’s disease

Abstract

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.

Cell Death-Related Ubiquitin Modifications in Inflammatory Syndromes: From Mice to Men

“…In a follow-up study, six more SHARPIN variants were identified from a cohort of 180 patients with LOAD and 184 patients with mild cognitive impairment ( Table 1 ). This, at present, is the only reported association between SHARPIN mutation and human diseases [ 59 ].…”

Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimer’s disease and amyotrophic lateral sclerosis

“…Most of the AD-associated SHARPIN variants cause amino acid replacements, whereas the AD-associated RBCK1 SNP (rs1358782) is an intron variant ( Bellenguez et al, 2022 ). Among them, the G186R and R274W variants of SHARPIN reportedly suppressed TNF-α-mediated NF-κB activation and generated aberrant granular clumps in HEK293T cells ( Asanomi et al, 2019 ; Asanomi et al, 2022 ). Moreover, the R274W variant of SHARPIN shows a weaker interaction with HOIP ( Park et al, 2021 ).…”

“…Due to these effects, the G186R mutation of SHARPIN would impair the formation of the LUBAC complex. Since the G186R mutation of SHARPIN reportedly resulted in aberrant intracellular localization and attenuated NF-κB activation ( Asanomi et al, 2019 ; Asanomi et al, 2022 ), the G186R mutation may cause dissociation of the LUBAC complex, and then the destabilized SHARPIN could form aggregates in the cell.…”

“…This simulation was validated by co-immunoprecipitation assays, which showed that the binding between SHARPIN UBL (R274W) and HOIP UBA1-UBA2 was significantly reduced, as compared with that of SHARPIN UBL WT ( Park et al, 2021 ). Furthermore, the R274W mutant of SHARPIN showed aberrant cellular localization and reduced activation of NF-κB ( Asanomi et al, 2022 ). The D291G mutation has also been reported as an AD-related SNP, but the D291 side chain is not directly involved in HOIP binding.…”

Identification of potential blood biomarkers for early diagnosis of Alzheimer’s disease through immune landscape analysis

“…The heritability of AD—that is, the presence of genetic risk factors—is estimated to be 60% to 80% 11 . A large number of genetic factors undoubtedly contribute to the etiopathogenesis and progression of AD, and some of them have been identified via whole-genome sequencing analyses 12 , 13 and genome-wide association studies 14 – 16 . The AD risk genes are implicated in the immune response ( CLU, CR1, CD33, EPHA1, MS4A4E/MS4A6A, ABCA7, PTK2B, TREM2 , and TREML2 ), endocytosis ( BIN1, PICALM , and CD2AP ), and lipid processing ( APOE, ABCA7 , and SORL1 ) 17 , 18 .…”