Browsing by Subject "DEGENERATION"

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  • Ahonen, Saija J.; Arumilli, Meharji; Lohi, Hannes (2013)
  • McWilliams, Thomas G.; Prescott, Alan R.; Villarejo-Zori, Beatriz; Ball, Graeme; Boya, Patricia; Ganleya, Ian G. (2019)
    Photoreception is pivotal to our experience and perception of the natural world; hence the eye is of prime importance for most vertebrate animals to sense light. Central to visual health is mitochondrial homeostasis, and the selective autophagic turnover of mitochondria (mitophagy) is predicted to play a key role here. Despite studies that link aberrant mitophagy to ocular dysfunction, little is known about the prevalence of basal mitophagy, or its relationship to general autophagy, in the visual system. In this study, we utilize the mito-QC mouse and a closely related general macroautophagy reporter model to profile basal mitophagy and macroautophagy in the adult and developing eye. We report that ocular macroautophagy is widespread, but surprisingly mitophagy does not always follow the same pattern of occurrence. We observe low levels of mitophagy in the lens and ciliary body, in stark contrast to the high levels of general MAP1LC3-dependent macroautophagy in these regions. We uncover a striking reversal of this process in the adult retina, where mitophagy accounts for a larger degree of the macroautophagy taking place, specifically in the photoreceptor neurons of the outer nuclear layer. We also show the developmental regulation of autophagy in a variety of ocular tissues. In particular, mitophagy in the adult mouse retina is reversed in localization during the latter stages of development. Our work thus defines the landscape of mitochondrial homeostasis in the mammalian eye, and in doing so highlights the selective nature of autophagy in vivo and the specificity of the reporters used.
  • Kyostila, Kaisa; Syrja, Pernilla; Jagannathan, Vidhya; Chandrasekar, Gayathri; Jokinen, Tarja S; Seppala, Eija H.; Becker, Doreen; Drogemuller, Michaela; Dietschi, Elisabeth; Drogemuller, Cord; Lang, Johann; Steffen, Frank; Rohdin, Cecilia; Jaderlund, Karin H.; Lappalainen, Anu K.; Hahn, Kerstin; Wohlsein, Peter; Baumgartner, Wolfgang; Henke, Diana; Oevermann, Anna; Kere, Juha; Lohi, Hannes; Leeb, Tosso (2015)
    Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10(-136)) in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to themacroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s) and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.
  • Cooper, Ann E.; Ahonen, Saija; Rowlan, Jessica S.; Duncan, Alison; Seppala, Eija H.; Vanhapelto, Paivi; Lohi, Hannes; Komaromy, Andras M. (2014)
  • Licht, Tamar; Kreisel, Tirzah; Biala, Yoav; Mohan, Sandesh; Yaari, Yoel; Anisimov, Andrey; Alitalo, Kari; Keshet, Eli (2020)
    Multiple insults to the brain lead to neuronal cell death, thus raising the question to what extent can lost neurons be replenished by adult neurogenesis. Here we focused on the hippocampus and especially the dentate gyrus (DG), a vulnerable brain region and one of the two sites where adult neuronal stem cells (NSCs) reside. While adult hippocampal neurogenesis was extensively studied with regard to its contribution to cognitive enhancement, we focused on their underestimated capability to repair a massively injured, nonfunctional DG. To address this issue, we inflicted substantial DG-specific damage in mice of either sex either by diphtheria toxin-based ablation of >50% of mature DG granule cells (GCs) or by prolonged brain-specific VEGF overexpression culminating in extensive, highly selective loss of DG GCs (thereby also reinforcing the notion of selective DG vulnerability). The neurogenic system promoted effective regeneration by increasing NSCs proliferation/survival rates, restoring a nearly original DG mass, promoting proper rewiring of regenerated neurons to their afferent and efferent partners, and regaining of lost spatial memory. Notably, concomitantly with the natural age-related decline in the levels of neurogenesis, the regenerative capacity of the hippocampus also subsided with age. The study thus revealed an unappreciated regenerative potential of the young DG and suggests hippocampal NSCs as a critical reservoir enabling recovery from catastrophic DG damage.
  • Colecchia, D; Stasi, M; Leonardi, M; Manganelli, F; Nolano, M; Veneziani, BM; Santoro, L; Eskelinen, Eeva-Liisa; Chiariello, M; Bucci, Cecilia (2018)
    Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy. In HeLa cells, we observed a reduced localization of all CMT2B-causing RAB7A mutants on autophagic compartments. Furthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7AV162M mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration.
  • Everson, Richard; Pettitt, Louise; Forman, Oliver P.; Dower-Tylee, Olivia; McLaughlin, Bryan; Ahonen, Saija; Kaukonen, Maria; Komaromy, Andras M.; Lohi, Hannes; Mellersh, Cathryn S.; Sansom, Jane; Ricketts, Sally L. (2017)
    The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10(-11)) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10(-19)). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a similar to 20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10(-27)). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function.
  • Ramsay, Eva; Ravina, Manuela; Sarkhel, Sanjay; Hehir, Sarah; Cameron, Neil R.; Ilmarinen, Tanja; Skottman, Heli; Kjems, Jrgen; Urtti, Arto; Ruponen, Marika; Subrizi, Astrid (2020)
    Inflammation is involved in the pathogenesis of several age-related ocular diseases, such as macular degeneration (AMD), diabetic retinopathy, and glaucoma. The delivery of anti-inflammatory siRNA to the retinal pigment epithelium (RPE) may become a promising therapeutic option for the treatment of inflammation, if the efficient delivery of siRNA to target cells is accomplished. Unfortunately, so far, the siRNA delivery system selection performed in dividing RPE cells in vitro has been a poor predictor of the in vivo efficacy. Our study evaluates the silencing efficiency of polyplexes, lipoplexes, and lipidoid-siRNA complexes in dividing RPE cells as well as in physiologically relevant RPE cell models. We find that RPE cell differentiation alters their endocytic activity and causes a decrease in the uptake of siRNA complexes. In addition, we determine that melanosomal sequestration is another significant and previously unexplored barrier to gene silencing in pigmented cells. In summary, this study highlights the importance of choosing a physiologically relevant RPE cell model for the selection of siRNA delivery systems. Such cell models are expected to enable the identification of carriers with a high probability of success in vivo, and thus propel the development of siRNA therapeutics for ocular disease.
  • Galli, Emilia; Lindholm, Päivi; Kontturi, Leena-Stiina; Saarma, Mart; Urtti, Arto; Yliperttula, Marjo (2019)
    Cerebral Dopamine Neurotrophic Factor (CDNF) shows beneficial effects in rodent models of Parkinson?s and Alzheimer?s disease. The brain is a challenging target for protein therapy due to its exclusive blood?brain barrier. Hence, the therapeutic protein should be delivered directly to the brain parenchyma. Implantation of encapsulated mammalian cells that constantly secrete CDNF is a potential approach for targeted and long-term protein delivery to the brain. In this study, we generated several CDNF-secreting cell clones derived from human retinal pigment epithelial cell line ARPE-19, and studied CDNF secretion from the clones maintained as monolayers and in polymeric microcapsules. The secretion of wild type (wt) CDNF transgene was low and the majority of the produced protein remained intracellular, locating mainly to the endoplasmic reticulum (ER). The secretion of wtCDNF decreased to even lower levels when the clones were in a non-dividing state, as in the microcapsules. Both codon optimization and deletion of the putative ER-retrieval signal (four last amino acids: KTEL) improved CDNF secretion. More importantly, the secretion of KTEL-deleted CDNF remained constant in the non-dividing clones. Thus, cells expressing KTEL-deleted CDNF, in contrast to wtCDNF, can be considered for cell encapsulation applications if the KTEL-deleted CDNF is proven to be biologically active in vivo.
  • Beyer, Hannes M.; Mikula, Kornelia M.; Kudling, Tatiana V.; Iwaï, Hideo (2019)
    Self-splicing inteins are mobile genetic elements invading host genes via nested homing endonuclease (HEN) domains. All HEN domains residing within inteins are inserted at a highly conserved insertion site. A purifying selection mechanism directing the location of the HEN insertion site has not yet been identified. In this work, we solved the three-dimensional crystal structures of two inteins inserted in the cell division control protein 21 of the hyperthermophilic archaea Pyrococcus abyssi and Pyrococcus horikoshii. A comparison between the structures provides the structural basis for the thermo-stabilization mechanism of inteins that have lost the HEN domain during evolution. The presence of an entire extein domain in the intein structure from Pyrococcus horikoshii suggests the selection mechanism for the highly conserved HEN insertion point.
  • Grabon, Aby; Orlowski, Adam; Tripathi, Ashutosh; Vuorio, Joni; Javanainen, Matti; Rog, Tomasz; Lönnfors, Max; McDermott, Mark I.; Siebert, Garland; Somerharju, Pentti; Vattulainen, Ilpo; Bankaitis, Vytas A. (2017)
    Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITP alpha, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITP alpha lipid exchange cycle: (i) interaction of PITP alpha with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITP alpha to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITP alpha; (iv) the trajectory of PtdIns or PtdCho into and through the lipidbinding pocket is chaperoned by sets of PITP alpha residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITP alpha PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the metazoan StART-like PITP family.
  • 99 Lives Consortium; Lohi, Hannes (2017)
    African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management.
  • Donner, Jonas; Anderson, Heidi; Davison, Stephen; Hughes, Angela M.; Bouirmane, Julia; Lindqvist, Johan; Lytle, Katherine M.; Ganesan, Balasubramanian; Ottka, Claudia; Ruotanen, Päivi; Kaukonen, Maria; Forman, Oliver P.; Fretwell, Neale; Cole, Cynthia A.; Lohi, Hannes (2018)
    Knowledge on the genetic epidemiology of disorders in the dog population has implications for both veterinary medicine and sustainable breeding. Limited data on frequencies of genetic disease variants across breeds exists, and the disease heritage of mixed breed dogs remains poorly explored to date. Advances in genetic screening technologies now enable comprehensive investigations of the canine disease heritage, and generate health-related big data that can be turned into action. We pursued population screening of genetic variants implicated in Mendelian disorders in the largest canine study sample examined to date by examining over 83,000 mixed breed and 18,000 purebred dogs representing 330 breeds for 152 known variants using a custom-designed beadchip microarray. We further announce the creation of MyBreedData (, an online updated inherited disorder prevalence resource with its foundation in the generated data. We identified the most prevalent, and rare, disease susceptibility variants across the general dog population while providing the first extensive snapshot of the mixed breed disease heritage. Approximately two in five dogs carried at least one copy of a tested disease variant. Most disease variants are shared by both mixed breeds and purebreds, while breed-or line-specificity of others is strongly suggested. Mixed breed dogs were more likely to carry a common recessive disease, whereas purebreds were more likely to be genetically affected with one, providing DNA-based evidence for hybrid vigor. We discovered genetic presence of 22 disease variants in at least one additional breed in which they were previously undescribed. Some mutations likely manifest similarly independently of breed background; however, we emphasize the need for follow up investigations in each case and provide a suggested validation protocol for broader consideration. In conclusion, our study provides unique insight into genetic epidemiology of canine disease risk variants, and their relevance for veterinary medicine, breeding programs and animal welfare.
  • Chen, Wei; Chen, Hao; Zheng, Dandan; Zhang, Hongbo; Deng, Lianfu; Cui, Wenguo; Zhang, Yuhui; Santos, Hélder A.; Shen, Hongxing (2020)
    Gene therapy provides an ideal potential treatment for intervertebral disk degeneration by delivering synthetic microRNAs (miRNAs) to regulate the gene expression levels. However, it is very challenging to deliver miRNAs directly, which leads to inactivation, low transfection efficiency, and short half‐life. Here, Agomir is loaded in hydrogel to construct a gene‐hydrogel microenvironment for regulating the synthesis/catabolism balance of the tissue extracellular matrix (ECM) to treat degenerative diseases. Agomir is a cholesterol‐, methylation‐, and phosphorothioate‐modified miRNA, which can mimic the function of miRNA to regulate the expression of the target gene. Agomir874 that mimics miRNA874 is synthesized to down regulate the expression of matrix metalloproteinases (MMPs) in nucleus pulposus (NP). At the same time, a polyethylene glycol (PEG) hydrogel is synthesized through Ag‐S coordination of 4‐arm PEG‐SH and silver ion solution, which has injectable, self‐healing, antimicrobial, degradable, and superabsorbent properties and matches perfectly with the mechanism of intervertebral disk. By delivering Agomir‐loaded PEG‐hydrogel to a degenerative intervertebral disk, a gene‐hydrogel microenvironment is constructed in situ, which reduces the expression of MMPs, regulates the synthesis/catabolism balance of ECM in the NP of the intervertebral disk, and improves the tissue microenvironment regeneration.
  • Evsyukov, Valentin; Domanskyi, Andrii; Bierhoff, Holger; Gispert, Suzana; Mustafa, Rasem; Schlaudraff, Falk; Liss, Birgit; Parlato, Rosanna (2017)
    Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human alpha-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/ PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T-SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known as RRN3) decrease in the substantia nigra of individuals with PD. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation of TIF-IA, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre-symptomatic stage. This is the first study to analyse nucleolar function in digenic PD models. We can conclude that, at least in these models, the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.
  • Kero, Mia; Raunio, Anna; Polvikoski, Tuomo; Tienari, Pentti J.; Paetau, Anders; Myllykangas, Liisa (2018)
    Background: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. Objective: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied. Methods: The population-based Vantaa 85(+) study includes all inhabitants of the city of Vantaa, who were > 85 years in 1991 (n = 601). Neuropathological assessment was possible in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE-staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau. Results: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p <0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p <0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated. Conclusion: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination.
  • Loukovaara, Sirpa; Haukka, Jari (2021)
    Purpose To examine whether real-world clinical patients with macular oedema (MO) receiving intravitreal antivascular endothelial growth factor (VEGF) therapy have a higher mortality compared with a matched reference population. Methods A population-based, retrospective cohort study of 26 386 patients from Finland, from January 1, 2001, to December 31, 2017. Index patients were identified through the Caring Epidemiology Project database, receiving at least one intravitreal anti-VEGF injection for wet age-related macular degeneration (AMD, n = 2243, 48.61%), diabetic MO (n = 744, 16.12%), MO due to retinal vascular occlusion (n = 589, 12.77%), or other MO (n = 1038, 22.5%). For each individual treated with intravitreal injection (n = 4614), five age- , sex- , calendar year- and hospital district- matched control individuals (n = 21 772) were chosen. Baseline data of chronic conditions were available. All-cause and cause-specific mortality was analysed using Cox ' s proportional hazards model. Results In general, the anti-VEGF treated patients had a higher prevalence of systemic conditions, including diabetes (60.1% vs. 46.8%, p <0.001), chronic hypertension (38.4% vs. 34.6%, p <0.001), in hospital-treated ischaemic heart disease (23.1% vs. 21.5%, p = 0.014), and glaucoma (11.1% vs. 6.3%, p <0.001) than controls. There was no difference in all-cause mortality between the anti-VEGF treated patients and matched controls (p = 0.62). In unadjusted Kaplan-Meier analysis of wet AMD subgroup, all-cause mortality was lower in anti-VEGF treated patients than matched controls (p = 0.015), but adjusted Cox ' s proportional hazards model showed no difference in the risk of all-cause mortality (HR 0.85, 95% CI 0.66-1.09). Conclusions Intravitreal anti-VEGF therapy was not associated with an increase in the risk of mortality in patients with MO compared with age- and sex-matched controls.
  • Shiri, Rahman; Euro, Ulla; Heliovaara, Markku; Hirvensalo, Mirja; Husgafvel-Pursiainen, Kirsti; Karppinen, Jaro; Lahti, Jouni; Rahkonen, Ossi; Raitakari, Olli T.; Solovieva, Svetlana; Yang, Xiaolin; Viikari-Juntura, Eira; Lallukka, Tea (2017)
    BACKGROUND: The purpose of this study is to assess the effects of lifestyle risk factors on the risk of hospitalization for sciatica and to determine whether overweight or obesity modifies the effect of leisure-time physical activity on hospitalization for sciatica. METHODS: We included 4 Finnish prospective cohort studies (Health 2000 Survey, Mobile Clinic Survey, Helsinki Health Study, and Young Finns Study) consisting of 34,589 participants and 1259 hospitalizations for sciatica during 12 to 30 years of follow-up. Sciatica was based on hospital discharge register data. We conducted a random-effects individual participant data meta-analysis. RESULTS: After adjustment for confounding factors, current smoking at baseline increased the risk of subsequent hospitalization for sciatica by 33% (95% confidence interval [CI], 13%-56%), whereas past smokers were no longer at increased risk. Obesity defined by body mass index increased the risk of hospitalization for sciatica by 36% (95% CI 7%-74%), and abdominal obesity defined by waist circumference increased the risk by 41% (95% CI 3%-93%). Walking or cycling to work reduced the risk of hospitalization for sciatica by 33% (95% CI 4%-53%), and the effect was independent of body weight and other leisure activities, while other types of leisure activities did not have a statistically significant effect. CONCLUSIONS: Smoking and obesity increase the risk of hospitalization for sciatica, whereas walking or cycling to work protects against hospitalization for sciatica. Walking and cycling can be recommended for the prevention of sciatica in the general population. (C) 2017 Elsevier Inc. All rights reserved.
  • Ignatenko, Olesia; Chilov, Dmitri; Paetau, Ilse; de Miguel, Elena; Jackson, Christopher B.; Capin, Gabrielle; Paetau, Anders; Terzioglu, Mugen; Euro, Liliya; Suomalainen, Anu (2018)
    Mitochondrial dysfunction manifests as different neurological diseases, but the mechanisms underlying the clinical variability remain poorly understood. To clarify whether different brain cells have differential sensitivity to mitochondrial dysfunction, we induced mitochondrial DNA (mtDNA) depletion in either neurons or astrocytes of mice, by inactivating Twinkle (TwKO), the replicative mtDNA helicase. Here we show that astrocytes, the most abundant cerebral cell type, are chronically activated upon mtDNA loss, leading to early-onset spongiotic degeneration of brain parenchyma, microgliosis and secondary neurodegeneration. Neuronal mtDNA loss does not, however, cause symptoms until 8 months of age. Findings in astrocyte-TwKO mimic neuropathology of Alpers syndrome, infantile-onset mitochondrial spongiotic encephalopathy caused by mtDNA maintenance defects. Our evidence indicates that (1) astrocytes are dependent on mtDNA integrity; (2) mitochondrial metabolism contributes to their activation; (3) chronic astrocyte activation has devastating consequences, underlying spongiotic encephalopathy; and that (4) astrocytes are a potential target for interventions.
  • Hariri, Amir H.; Velaga, Swetha B.; Girach, Aniz; Ip, Michael S.; Le, Phuc V.; Lam, Byron L.; Fischer, M. Dominik; Sankila, Eeva-Marja; Pennesi, Mark E.; Holz, Frank G.; Maclaren, Robert E.; Birch, David G.; Hoyng, Carel B.; Macdonald, Ian M.; Black, Graeme C.; Tsang, Stephen H.; Bressler, Neil M.; Larsen, Michael; Gorin, Michael B.; Webster, Andrew R.; Sadda, Srinivas R.; Nat Hist Progression Choroideremia (2017)
    PURPOSE: To identify valid and reproducible methods for quantifying anatomic outcome measures for eyes with choroideremia (CHM) in clinical trials. DESIGN: Reliability analysis study. METHODS: In this multicenter study, patients with confirmed genetic diagnosis of CHM were enrolled. All cases underwent spectral-domain optical coherence tomography (SDOCT) and fundus autofluorescence (FAF) imaging. Two graders independently delineated boundaries of preserved autofluorescence (PAF) and pre-served ellipsoid zone (EZ) on FAF and OCT images, respectively. The results of the 2 independent gradings of both FAF and OCT images were compared to assess the reproducibility of the grading methods. RESULTS: A total of 148 eyes from 75 cases were included. In 21% of eyes PAF and in 43% of eyes preserved EZ had extended beyond the image capture area. After exclusion of these eyes and low-quality images, 114 FAF and 77 OCT images were graded. The mean PAF areas from 2 independent gradings were 3.720 +/- 3.340 mm(2) and 3.692 +/- 3.253 mm2, respectively. Intraclass correlation coefficient (ICC) for these gradings was 0.996. The mean preserved EZ areas from 2 independent gradings were 2.746 +/- 2.319 mm2 and 2.858 2.446 mm2, respectively. ICC for these gradings was 0.991. CONCLUSIONS: Quantifying preserved retinal pigment epithelium and EZ areas on FAF and OCT images, respectively, in CHM patients is highly reproducible. These variables would be potential anatomic outcome measures for CHM clinical trials and could be studied and tracked longitudinally in choroideremia. (C) 2017 Elsevier Inc. All rights reserved.