Showing papers by "Jan O. Aasly published in 2019"
19 citations
TL;DR: The findings suggest that a novel mutation in MCM3AP is associated with hypokalemic PP, a protein involved in the export of certain messenger RNAs from the nucleus to the cytoplasm.
Abstract: Introduction Primary periodic paralyses (PPs) are rare genetic neuromuscular disorders commonly caused by mutations in genes related to ion channel function. However, 10%-20% of cases remain as genetically unexplained. Herein we present a family with PP with paralytic episodes generally lasting for 1-7 days at a time, associated with a drop in K+ levels. Methods Screening for mutations in known disease-causing genes was negative, hence we performed whole-exome sequencing of 5 family members. Results Minichromosome maintenance 3-associated protein (MCM3AP) c.2615G>A (p.C872Y) was found to cosegregate with disease in the family and was not present in control subjects. The mutation is novel, highly conserved across multiple species, and predicted to be damaging. Discussion MCM3AP encodes germinal center-associated nuclear protein (GANP), a protein involved in the export of certain messenger RNAs from the nucleus to the cytoplasm. Our findings suggest that a novel mutation in MCM3AP is associated with hypokalemic PP. Muscle Nerve, 2019.
2 citations
TL;DR: The data revealHDAC6 as a target of LRRK2 and suggest that deregulation of HDAC6-mediated aggresome formation and aggrephagy could contribute to the pathology of PD.
Abstract: Mutations in LRRK2 are the most common cause of dominantly inherited Parkinson’s disease (PD). A proportion of LRRK2 PD exhibits Lewy pathology with accumulations of α-synuclein and ubiquitin in intracellular aggregates that are indistinguishable from idiopathic PD. LRRK2 is a multi-domain protein with both GTPase and kinase activities that has been shown to affect various cellular processes including protein homeostasis, however how PD mutations in LRRK2 may lead to accumulation of ubiquitinated protein aggregates remains unclear. A main cellular pathway to remove aggregated ubiquitinated proteins is aggrephagy: the histone deacetylase HDAC6 recognizes ubiquitinated misfolded proteins and recruits them to the molecular motor cytoplasmic dynein which transports them to the perinuclear region where they are trapped in aggresomes that are subsequently removed by macroautophagy. Here we identified HDAC6 as a novel LRRK2 substrate and show that LRRK2 regulates HDAC6-dependent aggresome formation. LRRK2 directly interacted with the HDAC6 deacetylase domains via its Roc domain and phosphorylated HDAC6 on serine-22. Serine-22 phosphorylation of HDAC6 enhanced its interaction with cytoplasmic dynein and stimulated recruitment of ubiquitinated proteins to aggresomes. Knockdown or knockout of LRRK2 impaired HDAC6-mediated aggresome formation. PD mutant LRRK2 G2019S showed reduced interaction with HDAC6 and did not support aggresome formation to the same extend as wild type LRRK2. This was recapitulated in LRRK2 G2019S patient-derived iAstrocytes that showed an aggresome formation defect. In conclusion our data reveal HDAC6 as a target of LRRK2 and suggest that deregulation of HDAC6-mediated aggresome formation and aggrephagy could contribute to the pathology of PD.
1 citations