BackgroundNeuronal ceroid lipofuscinoses (NCLs) comprise at least eight genetically characterized neurodegenerative disorders of childhood. Despite of genetic heterogeneity, the high similarity of clinical symptoms and pathology of different NCL disorders suggest cooperation between different NCL proteins and common mechanisms of pathogenesis. Here, we have studied molecular interactions between NCL proteins, concentrating specifically on the interactions of CLN5, the protein underlying the Finnish variant late infantile form of NCL (vLINCLFin).ResultsWe found that CLN5 interacts with several other NCL proteins namely, CLN1/PPT1, CLN2/TPP1, CLN3, CLN6 and CLN8. Furthermore, analysis of the intracellular targeting of CLN5 together with the interacting NCL proteins revealed that over-expression of PPT1 can facilitate the lysosomal transport of mutated CLN5FinMajor, normally residing in the ER and in the Golgi complex. The significance of the novel interaction between CLN5 and PPT1 was further supported by the finding that CLN5 was also able to bind the F1-ATPase, earlier shown to interact with PPT1.ConclusionWe have described novel interactions between CLN5 and several NCL proteins, suggesting a modifying role for these proteins in the pathogenesis of individual NCL disorders. Among these novel interactions, binding of CLN5 to CLN1/PPT1 is suggested to be the most significant one, since over-expression of PPT1 was shown to influence on the intracellular trafficking of mutated CLN5, and they were shown to share a binding partner outside the NCL protein spectrum.

Background: Neuronal ceroid lipofuscinoses (NCLs) are collectively the most common type of recessively inherited childhood encephalopathies. The most severe form of NCL, infantile neuronal ceroid lipofuscinosis (INCL), is caused by mutations in the CLN1 gene, resulting in a deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1). The deficiency of PPT1 causes a specific death of neocortical neurons by a mechanism, which is currently unclear. To understand the function of PPT1 in more detail, we have further analyzed the basic properties of the protein, especially focusing on possible differences in non-neuronal and neuronal cells.

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disease caused by deficiency of palmitoyl protein thioesterase 1 (PPT1). INCL results in dramatic loss of thalamocortical neurons, but the disease mechanism has remained elusive. In the present work we describe the first interaction partner of PPT1, the F(1)-complex of the mitochondrial ATP synthase, by co-purification and in vitro-binding assays. In addition to mitochondria, subunits of F(1)-complex have been reported to localize in the plasma membrane, and to be capable of acting as receptors for various ligands such as apolipoprotein A-1. We verified here the plasma membrane localization of F(1)-subunits on mouse primary neurons and fibroblasts by cell surface biotinylation and TIRF-microscopy. To gain further insight into the Ppt1-mediated properties of the F(1)-complex, we utilized the Ppt1-deficient Ppt1(Delta ex4) mice. While no changes in the mitochondrial function could be detected in the brain of the Ppt1(Delta ex4) mice, the levels of F(1)-subunits alpha and beta on the plasma membrane were specifically increased in the Ppt1(Delta ex4) neurons. Significant changes were also detected in the apolipoprotein A-I uptake by the Ppt1(Delta ex4) neurons and the serum lipid composition in the Ppt1(Delta ex4) mice. These data indicate neuron-specific changes for F(1)-complex in the Ppt1-deficient cells and give clues for a possible link between lipid metabolism and neurodegeneration in INCL.

Background Nonsteroidal anti‐inflammatory drug (NSAID) exacerbated respiratory disease (N‐ERD) is a triad with asthma, chronic rhinosinusitis with nasal polyps, and NSAID intolerance. Uncontrolled N‐ERD forms a major public health problem due to frequent and difficult‐to‐treat exacerbations and/or requiring putatively frequent endoscopic sinus surgeries (ESS). Our aim was to study factors affecting control of N‐ERD. Methods Retrospective patient record data (patient characteristics, prior sinus surgeries, follow‐up data in 2020) from 167 N‐ERD patients undergoing consultation at three tertiary hospitals from 2001 to 2017 was used. Outcome measurements reflecting uncontrolled N‐ERD were revision ESS, corticosteroids/biological therapy, and antibiotic courses during 2016–2020. Associations were analyzed by using nonparametric tests, Cox's proportional hazard, and binary logistic regression models. Results Nasal polyp eosinophilia increased the risk of revision surgery during the follow‐up (adjusted hazard ratio [aHR] 3.21, confidence interval 1.23–8.38). Also baseline oral corticosteroids (OCS; HR, 1.73, 1.04–2.89) and baseline surgery without total ethmoidectomy increased the risk of revision ESS (HR, 2.17, 1.07–4.42) in unadjusted models. In addition, both baseline OCS (adjusted odds ratio [aOR] 2.78, 1.23–6.26) and a history of ≥4 previous ESS (aOR, 2.15, 0.98–4.70) were associated with the use of OCS/biological therapy during the follow‐up, but not with high number of antibiotics. Conclusions Nasal polyp eosinophilia, baseline OCS, and a history of recurrent ESS predict uncontrolled N‐ERD. These factors might be clinically useful in risk‐estimation of uncontrolled disease and for organizing follow‐ups. Prospective cohort studies with larger sample size are needed to further study the factors affecting the upper airway control of N‐ERD.