Browsing by Subject "ALS"

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  • Murphy, Natalie A.; Arthur, Karissa C.; Tienari, Pentti J.; Houlden, Henry; Chio, Adriano; Traynor, Bryan J. (2017)
    A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.
  • Hella, Emilia (Helsingfors universitet, 2015)
    This review focuses on neurotrophic factors, especially CDNF, and Amyotropic lateral sclerosis (ALS). This review finds out which neurotrophic factors have been studied in clinical trials of ALS and what kind of results have been got. Neurotrophic factors are important for development and function of neurons because they prevent apoptosis of neurons. They also play role in differentiation, development and migration of neurons. It is also known that many of the neurotrophic factors have protective and restorative properties. ALS is a rare neurodegenerative disease which causes the destruction of motor neurons and leads to death in three years. The disease degenerate the upper and lower motor neurons. Symptoms are muscle weakness, muscle atrophy, cramps and problems with swallowing. At the moment there is no cure for ALS so it is important to study neurotrophic factors that could prevent the progression of the disease and perhaps to protect or repair destroyed motor neurons. This is why it is important to study potential of CDNF in ALS. The experimental part consists of three different parts. The purpose of the first part study was to determine the distribution of CDNF after intraventricular delivery at different time points. CDNF was labeled with 125I (125I-CDNF). The distribution was determined by gammacounter and autoradiography. To determine the stability of the injected 125-I CDNF we performed SDS-PAGE. The second part studied the diffusion volume of CDNF after intraventricular injection with seven wild type mice. After stereotaxic surgery CDNF-immunohistochemistry staining from coronal sections was done. The last experimental part studied the effect of single intracerebral injection of CDNF on motivation, locomotor activity, anxiety and depression with male and female mice. Light-dark box, open field, rotarod, forced swim test (FST), elevated plus maze and fear conditioning were carried out with male mice. After behavioural tests mice were sacrified for HPLC-analysis. Light-dark box and IntelliCage were carried out with female mice before c-fos staining. Gammacounter and autoradiography shows that 125I-CDNF distributes widely after intracerebroventricular injection. It spread throughout to the brain and also all the way to the spinal cord after one and three hours from injection. After 24 hours 125I-CDNF was cleared so the CDNF signal was very weak. SDS-PAGE showed the stability of radioactive CDNF. CDNF increased locomotor activity and decreased anxiety in male mice. But a statistically significant difference appeared in forced swim test and fear conditioning test. HPLC-analysis supported these results partly. CDNF also increased motivation of female mice in IntelliCage experiment. C-fos staining was observed in CDNF group and PBS group so quantitative analysis should be done from these sections so that reliable conclusions could be done. However, because CDNF distributed to spinal cord and it showed some effect on locomotor activity, motivation and depression it might be potential for ALS disease.
  • Harjuhaahto, Sandra; Rasila, Tiina S.; Molchanova, Svetlana M.; Woldegebriel, Rosa; Kvist, Jouni; Konovalova, Svetlana; Sainio, Markus T.; Pennonen, Jana; Torregrosa-Munumer, Ruben; Ibrahim, Hazem; Otonkoski, Timo; Taira, Tomi; Ylikallio, Emil; Tyynismaa, Henna (2020)
    Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and axonal neuropathy and in Parkinson's disease. They form a complex of unknown function. Here we address the importance of these two proteins in human motor neurons. We show that gene edited human induced pluripotent stem cells (iPSC) lacking either CHCHD2 or CHCHD10 are viable and can be differentiated into functional motor neurons that fire spontaneous and evoked action potentials. Mitochondria in knockout iPSC and motor neurons sustain ultrastructure but show increased proton leakage and respiration, and reciprocal compensatory increases in CHCHD2 or CHCHD10. Knockout motor neurons have largely overlapping transcriptome profiles compared to isogenic control line, in particular for synaptic gene expression. Our results show that the absence of either CHCHD2 or CHCHD10 alters mitochondrial respiration in human motor neurons, inducing similar compensatory responses. Thus, pathogenic mechanisms may involve loss of synaptic function resulting from defective energy metabolism.
  • Rautiola, Jesper (Helsingin yliopisto, 2021)
    Amyotrofinen lateraaliskleroosi (ALS) on etenevä, kuolemaan johtava, neurodegeneratiivinen sairaus, jolle tyypillistä on raaja-alkuinen lihasheikkous, lihasjäykkyys ja atrofia. Noin 25-30% potilaista sairastaa bulbaarialkuista tautia, jolle tyypillistä on puheentuoton ja nielemisen häiriöt. Taudin esiintyvyys Euroopassa on 4.1-8.2 tapausta 100 000 henkilövuotta kohden. Tämän tutkimuksen tavoitteena oli selvittää ensisijaisesti korva-, nenä- ja kurkkutaudeille hakeutuvien ALS-potilaiden ja erityisesti bulbaarista tautia sairastavien potilaiden tyypillinen oirekirjo, mahdollinen läheteviive ja taudin kulku sekä nielemisfunktiotutkimusten käyttökelpoisuus ja hoidon tulokset. Toissijainen tavoite oli selvittää parenteraalisen ravitsemuksen ja trakeostomian esiintyvyys koko potilasryhmässä. Tutkimusta varten kerättiin kaikki Helsingin ja Uudenmaan sairaanhoitopiirin diagnosoidut ALS-potilaat vuosilta 2010–2014, joita oli yhteensä 327, ja näistä 110 bulbaari-ALS-potilaita. Kaikista potilaista selvitettiin sukupuoli, taudin tyyppi ja kesto, tehdyt toimenpiteet, ja lisäksi bulbaarialkuista tautia sairastavilta nielemisfunktiotutkimuksiin, hengitys- ja nielemisoireiden alkuun, ensimmäiseen hoitokontaktiin, erikoislääkärikontaktiin sekä ensimmäiseen neurologikontaktiin liittyvää dataa. Aineisto analysoitiin käyttäen vakiintuneita tilastollisia menetelmiä. Tutkimuksessa selvisi, että korva-, nenä- ja kurkkutaudeille tyypillisesti hakeudutaan bulbaarialkuisen taudin tyyppioireiden takia. ALS-potilaiden hoitotulokset eivät merkittävästi riipu siitä, mille erikoisalalle potilas ensimmäisenä lähetetään. Lisäksi taudin insidenssi, hoitotulokset ja tehtyjen toimenpiteiden kumulatiivinen insidenssi vastaa kirjallisuuskatsauksessa ilmeneviä eurooppalaisia lukuja. Tutkimuksemme perusteella parenteraalinen ravitsemus näyttää parantavan bulbaarialkuista tautia sairastavan elinajan ennustetta, mutta hieman yllättäen huonontavan raaja-alkuista tautia sairastavan potilaan elinajan ennustetta. Tutkimus selkeyttää korva-, nenä- ja kurkkutautilääkäreille hakeutuvien potilaiden oirekuvaa ja selvittää ALS:n hoidon tilaa ja tuloksia Suomessa.
  • Peltola, Roosa (Helsingin yliopisto, 2020)
    Amyotrophic lateral sclerosis (ALS) is a rare fatal neurodegenerative disease in which both the upper and lower motor neurons degenerate. Pathological features of the disease include misfolded proteins and accumulations in the central nervous system. The molecular mechanisms of the disease include neuroinflammation, glutamate induced excitotoxicity, and endoplasmic reticulum stress (ER-stress). Numerous genetic defects have been identified in the background of ALS, the most common mutations are in the C9ORF72, SOD1, TDP43 and FUS genes. For each gene mutation, it is important to develop a reliable animal model of ALS for studying pathology and testing new therapies. The most common and most recently found gene mutation, the C9ORF72 repeat expansion mutation, does not yet have an established animal disesase model. The molecular mechanisms of the disease include neuroinflammation, glutamate induced excitotoxicity, and endoplasmic reticulum stress (ER- stress). There is no drug treatment to cure or slow ALS, so the need for new drug therapies that affect the course of the disease is significant. Cerebral dopamine neurotrophic factor (CDNF) protects and restores dopamine neurons and controls ER-stress in preclinical models of Parkinson’s disease. CDNF has also been shown to improve motor coordination as well as protect spinal cord neurons from cell destruction in ALS genetic SOD1- G93A mouse and TDP-43M337 animal models. The purpose of this master's thesis study was to characterize the changes related to neurodegeneration and neuroinflammation in the new C9ORF72-500 disease model and study ER stress of the SOD1-93A disease model and the effect of CDNF on ER stress in SOD1-model and on inflammation in C9-model. In the first sub-study, brain sections from C9ORF72 transgenic and wild-type mice at different time points were subjected to six different immunohistological stainings. The results were compared at each time point (30, 70 and 170) between the wild type and the transgenic group. In another sub-study, spinal cord sections from CDNF snd vehicle treated SOD1- G93A mice were subjected to immunofluorescence staining, after which the intensity of their ER stress marker, GRP78, was analyzed using a confocal microscope. GFAP stained brain sections from CDNF and vehicle treated C9ORF72 mice were analyzed using microscope and imaging analyses. The results of the first sub-study showed neuroinflammation at 24 weeks timepoint in the transgenic group compared to wild-type mice. Pathological features of C9-ALS, various protein accumulations, were observed only in the transgenic group, mainly at 24 weeks. No neuronal loss was observed in this study. The obtained results support the previously published research results and support the reliability of the studied disease model. In the second sub-study ER stress levels were higher in SOD1-mice compared to wild-type mice. Single intracerebroventrical CDNF injection reduced ER stress in SOD1-G93A transgenic mice almost to the same level as ER stress in wild-type mice. CDNF treatment also showed a tendency for reducing inflammation in hippocampus and motor cortex of C9ORF72 mice. The results confirm the pathological role of ER stress in ALS and show that CDNF reduces ER stress when administered as early in the disease as possible, when neuronal damage begins to occur but does not yet lead to neuronal destruction. CDNF appears to be a promising drug candidate for the treatment of ALS and should therefore be further investigated.
  • Project MinE ALS GWAS Consortium I; Schijven, Dick; Stevelink, Remi; McCormack, Mark; van Rheenen, Wouter; Luykx, Jurjen J.; Koeleman, Bobby P. C.; Veldink, Jan H.; Eriksson, Johan G.; Kälviäinen, Reetta; Kantanen, Anne-Mari; Lehesjoki, Anna-Elina; Palotie, Aarno (2020)
  • Yu, Xiaowei; Litkey, Paula; Hyyppa, Juha; Holopainen, Markus; Vastaranta, Mikko (2014)
  • Valkonen, Konsta Valentin (Helsingin yliopisto, 2021)
    Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motoneuron disease. ALS is characterized by a progressive loss of upper and lower motoneurons, resulting in muscle atrophy, paralysis and ultimately in death. Approximately 30,000 people die of ALS annually. There is no cure for ALS, and only two drugs - riluzole and edavarone - have been approved for the treatment of the disease. The complex pathology of ALS contributes to the lack of effective treatments. Several cellular pathologies have been suggested to contribute to the pathogenesis, including ER stress, disruption of calcium homeostasis, oxidative stress and excitotoxicity. Here we describe the cytoprotective effects of C-terminal fragments of the novel proteins with neurotrophic factor properties MANF (mesencephalic astrocyte-derived neurotrophic factor) and CDNF (cerebral dopamine neurotrophic factor) on a toxin model of ALS in vitro. Unlike the classical neurotrophic factors, MANF and CDNF are predominantly localized to the endoplasmic reticulum (ER) and have been shown to alleviate ER stress by keeping the unfolded protein response (UPR) transducers inactive. ER stress is a major component in many neurodegenerative diseases, including ALS, and is a promising therapeutic target for MANF and CDNF. However, the potential of these proteins in ALS treatment remains to be insufficiently described. We used differentiated motoneuron-like NSC-34 cells treated with a range of toxins, modelling different cellular pathologies linked to ALS. After the toxin addition, we treated the cells with MANF and CDNF variants and riluzole and measured the cell viability. The toxin panel consists of tunicamycin, ionomycin and staurosporine. Tunicamycin causes cell death by activating proapoptotic branches of the UPR. Ionomycin is an ionophore and depletes the ER of calcium, thus inducing both UPR-dependent and UPR-independent apoptosis. Less is known about the mechanisms of staurosporine, but it has been shown to induce caspase-3-dependent apoptosis, increase intracellular calcium levels and cause oxidative stress. We hypothesized that both MANF and CDNF variants protect the cells against UPR-dependent apoptosis but not against UPR-independent cell death. We show that MANF and CDNF variants protect the cells against apoptosis induced by tunicamycin, ionomycin and staurosporine. Interestingly, the protein variants mediated the highest protection against ionomycin-induced stress, and they exhibited mild protective effects against staurosporine as well. These findings suggest that MANF and CDNF variants might have a role in maintaining intracellular calcium homeostasis. However, it is possible that staurosporine induces ER stress as well, which would explain the protection conferred by the protein variant. We report that the CDNF variant mediates higher protection at lower concentrations compared to the MANF variant in every toxin assay, whereas the MANF variant mediates higher protection at the highest tested concentration compared to the CDNF variant. We also show that the CDNF variant-mediated protection against staurosporine-induced stress peaked at lower concentrations, and the highest concentration provided distinctively lower, yet significant effect. These data lead us to hypothesize that the protein variants may have a slightly different mode of action, and that they might provide an additive effect when administered simultaneously. We tested a combination of MANF and CDNF variants in cells treated with tunicamycin, ionomycin and staurosporine. However, the combination treatment did not increase the viability more than MANF and CDNF variants independently did. The results answered our questions as well as raised new ones. In the future, the putative calcium-regulating effects of the protein variants should be investigated. The UPR-modifying effects of the drug candidates and toxins need to be assessed by quantifying changes in the UPR marker mRNA and protein expression levels. If it is revealed that the variants have a different mode of action, the possible additive protective effects must be assessed. Finally, a wider toxin panel is needed to fully explore the potential of MANF and CDNF variants in ALS treatment. This study demonstrates the potential of MANF and CDNF variants in protecting motoneurons against several pathological pathways contributing to ALS pathology. However, the mechanisms of action of the variants need further investigation to fully understood their therapeutic potential.
  • Kaivola, Karri; Salmi, Samuli J; Jansson, Lilja; Launes, Jyrki; Hokkanen, Laura; Niemi, Anna-Kaisa; Majamaa, Kari; Lahti, Jari; Eriksson, Johan G; Strandberg, Timo; Laaksovirta, Hannu; Tienari, Pentti J (BioMed Central, 2020)
    Abstract The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.
  • Kaivola, Karri; Salmi, Samuli J.; Jansson, Lilja; Launes, Jyrki; Hokkanen, Laura; Niemi, Anna-Kaisa; Majamaa, Kari; Lahti, Jari; Eriksson, Johan G.; Strandberg, Timo; Laaksovirta, Hannu; Tienari, Pentti J. (2020)
    The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson's disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7-45, 17-45, 21-45, 24-45 and 24-30). The carriership of an intermediate-length allele did not associate with ALS (Fisher's test, all p >= 0.15) nor was there any association with survival (p >= 0.33), when we divided our control group into three age groups (18-65, 66-84 and 85-105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was >= 17 repeats (p=0.002, OR 5.32 95% CI 2.02-14.05) or >= 21 repeats (p=0.00016, OR 15.21 95% CI 3.79-61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.
  • Tallberg, Thomas (Helsingfors universitet, 2017)
    Transactive DNA Response Element Binding Protein 43 (TDP-43) is a RNA binding protein participating in gene expression on a transcriptional level. It is localized in the cell nucleus. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons. In most ALS patients TDP-43 becomes localized into the cytoplasm of neurons and glia cells. The TDP-43 rat ALS model provide insight in ALS disease progression and molecular mechanisms. This animal model has been characterized previously in the literature. Cerebral Dopamine Growth Factor (CDNF) is a neuroprotective and restorative protein in rat animal model of Parkinson's disease. CDNF may have an impact on disease progression in ALS. One of the goals in this work was to recharacterize the TDP-43 rat ALS model and to try repeat published data. The other aim of this work was to treat TDP-43 rats with intraventricular chronic infusion of CDNF, and to compare symptom progression with TDP-43 rats treated with phosphate buffered saline. Behavioral assays were done trice a week and when rats reached endpoint, spinal cords were removed. Motor neuron counting and detection of stress granule formation were investigated in spinal cords with immunohistochemistry. Also, the volume of CDNF diffusion in rat brain after chronic intraventricular CDNF infusion was investigated with immunohistochemistry. In the characterization part, symptom progression was repeated in a similar manner as it has been reported previously. CDNF treatment could not stop the symptom progression nor slow down the progression of symptoms in TDP-43 rats. Motor neuron counting revealed a heavy loss of motor neurons in the lumbal part of the spinal cord in both treatment groups. Diffusion of CDNF was very poor in the rat brain. Higher doses of CDNF and proper administration depth in the brain or route of administration should be reconsidered in the future.
  • Montonen, Ella (Helsingfors universitet, 2015)
    Endoplasmic reticulum stress (ER-stress) is the result of accumulation of unfolded and misfolded proteins in the ER. The unfolded proteins activate the unfolded protein response (UPR), which seeks to reduce the protein load in the ER and reduces ER-stress. When ER-stress is prolonged, the UPR will activate apoptosis. Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease that affects lower and higher motorneurons. The cause of ALS is unknown but ER-stress is known to play a role in the disease progression. CDNF is a new neurotrophic factor, which is known to play a role in protein folding in the ER. CDNF is neuroprotective and neurorestorative in animal models of Parkinson's disease. Thus, CDNF is a potential new drug candidate for treating ALS. The aim of this work was to examine the effect of CDNF on disease state and life span in transgenic SOD1(G93A)-mice. CDNF or PBS was injected into the mouse's ventricle in stereotaxic surgery when the mice were about 90 days old. Clinical status and motor coordination was monitored twice a week throughout the study. The mice were dissected when they reached the end point that was set for the study. Deepfrozen gastrocnemius muscles were stained with antibodies, to examine the integrity of the neuromuscular junctions (NMJ). Quantitative PCR (qPCR) was executed on deepfrozen spinal cord and motor cortex samples to measure the expression of ER-stress genes. The results showed that CDNF improves motor coordination and delays disease progression in SOD1 female mice. The NMJs were notably more damaged in SOD1 mice than in wild type mice, but CDNF did not have any significant effect on NMJ integrity. ER-stress could be observed in the spinal cord and motor cortex of SOD1 mice and CDNF decreased ER-stress in the motor cortex. CDNF did not decrease ER-stress in the spinal cord where the expression of apoptosis related genes was increased. Thus, CDNF is a potential new drug candidate for treating ALS and it should be studied further.
  • Korpelainen, Anna (Helsingfors universitet, 2019)
    Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease in which both upper and lower motor neurons degenerate gradually. The disease leads to a total paralysis of almost all skeletal muscles and to death within 3-5 years after onset. At the moment there are two disease modifying medicines available, riluzole and edaravone. Neither is able to cure the disease or even to stop or remarkably slow down its progression. Endoplasmic reticulum (ER) stress has been proposed as one of the pathophysiological mechanisms underlying ALS. During ER stress misfolded of unfolded proteins accumulate in ER lumen. As a defense mechanism, the cell launches unfolded protein response (UPR). UPR response aims to reduce the protein load in ER and restore cell’s normal functions. If the damage is already beyond repair, UPR signal cascades lead to programmed cell death. Neurotrophic factors (NTFs) regulate the growth of nervous tissue and participate in repairing processed. Many of the known NTFs have first seemed promising in the preclinical models of ALS but however failed in clinical trials. Cerebral dopamine neurotrophic factor (CDNF) differs drastically both in structure and function from conventional NTFs. CDNF has seen to relieve ER stress and improve motor behavior in the animal models of Parkinsons’s disease. Recently CDNF entered clinical trials in Parkinson’s patients. Since ER stress is believed to be present not only in ALS but also in Parkinson’s disease and other neurodegenerative diseases, it might have an effect in treating ALS patients. SOD1-G93A is a well-established animal model of ALS in which the animals show typical motor impairments comparable to human disease. In this study we used a novel mouse line obtained from crossing traditional SOD1-G93A model and CDNF knock out models. The study aimed to evaluate the effect of endogenic CDNF loss in survival, onset of symptoms, motor behavioral and spinal motor neuron degeneration in the new line. ER-stress and autophagy marker levels were studied with quantitative polymerase chain reaction (CNDF) and western blotting techniques. Spinal motor neuron loss was examined by anti-choline acetyltransferase antibody (ChAT) stainings. SOD1-G93A CDNF knock out animals were observed to have more severe motor impairments in the early stages of the disease compared to the traditional SOD1-G93A mice. In addition, the degeneration of spinal motor neurons appeared to be more severe in the new line. There were no statistically significant differences in ER stress between the genotypes although a trend of increased ER stress was observed. Endogenous CDNF loss had no effect on the healthy animals. The results suggest that CNDF is a potential treatment for ALS and it might have only little side effect since it does not seen to affect healthy tissue. In medical usage, CDNF might be most effective when administered immediately after disease onset. However, this might be difficult because of the challenges in ALS diagnosis.
  • Kantola, Tuula; Vastaranta, Mikko; Yu, Xiaowei; Lyytikäinen-Saarenmaa, Päivi; Holopainen, Markus; Talvitie, Mervi; Kaasalainen, Sanna; Solberg, Svein; Hyyppä, Juha (2010)
    Climate change and rising temperatures have been observed to be related to the increase of forest insect damage in the boreal zone. The common pine sawfly (Diprion pini L.) (Hymenoptera, Diprionidae) is regarded as a significant threat to boreal pine forests. Defoliation by D. pini can cause severe growth loss and tree mortality in Scots pine (Pinus sylvestris L.) (Pinaceae). In this study, logistic LASSO regression, Random Forest (RF) and Most Similar Neighbor method (MSN) were investigated for predicting the defoliation level of individual Scots pines using the features derived from airborne laser scanning (ALS) data and aerial images. Classification accuracies from 83.7% (kappa 0.67) to 88.1% (kappa 0.76) were obtained depending on the method. The most accurate result was produced using RF with a combination of data from the two sensors, while the accuracies when using ALS and image features separately were 80.7% and 87.4%, respectively. Evidently, the combination of ALS and aerial images in detecting needle losses is capable of providing satisfactory estimates for individual trees.
  • Kantola, Tuula; Vastaranta, Mikko; Lyytikäinen-Saarenmaa, Päivi; Holopainen, Markus; Kankare, Ville; Talvitie, Mervi; Hyyppä, Juha (2013)
    Forest disturbances caused by pest insects are threatening ecosystem stability, sustainable forest management and economic return in boreal forests. Climate change and increased extreme weather patterns can magnify the intensity of forest disturbances, particularly at higher latitudes. Due to rapid responses to elevating temperatures, forest insect pests can flexibly change their survival, dispersal and geographic distributions. The outbreak pattern of forest pests in Finland has evidently changed during the last decade. Projection of shifts in distributions of insect-caused forest damages has become a critical issue in the field of forest research. The Common pine sawfly (Diprion pini L.) (Hymenoptera, Diprionidae) is regarded as a significant threat to boreal pine forests. Defoliation by D. pini has resulted in severe growth loss and mortality of Scots pine (Pinus sylvestris L.) (Pinaceae) in eastern Finland. In this study, tree-wise defoliation was estimated for five different needle loss category classification schemes and for 10 different simulated airborne laser scanning (ALS) pulse densities. The nearest neighbor (NN) approach, a nonparametric estimation method, was used for estimating needle loss of 701 Scots pines, using the means of individual tree features derived from ALS data. The Random Forest (RF) method was applied in NN-search. For the full dense data (~20 pulses/m2), the overall estimation accuracies for tree-wise defoliation level varied between 71.0% and 86.5% (kappa-values of 0.56 and 0.57, respectively), depending on the classification scheme. The overall classification accuracies for two class estimation with different ALS pulse densities varied between 82.8% and 83.7% (kappa-values of 0.62 and 0.67, respectively). We conclude that ALS-based estimation of needle losses may be of acceptable accuracy for individual trees. Our method did not appear sensitive to the applied pulse densities.
  • White, Joanne C.; Saarinen, Ninni; Kankare, Ville; Wulder, Michael A.; Hermosilla, Txomin; Coops, Nicholas C.; Pickell, Paul D.; Holopainen, Markus; Hyyppä, Juha; Vastaranta, Mikko (2018)
    Landsat time series (LTS) enable the characterization of forest recovery post-disturbance over large areas; however, there is a gap in our current knowledge concerning the linkage between spectral measures of recovery derived from LTS and actual manifestations of forest structure in regenerating stands. Airborne laser scanning (ALS) data provide useful measures of forest structure that can be used to corroborate spectral measures of forest recovery. The objective of this study was to evaluate the utility of a spectral index of recovery based on the Normalized Burn Ratio (NBR): the years to recovery, or Y2R metric, as an indicator of the return of forest vegetation following forest harvest (clearcutting). The Y2R metric has previously been defined as the number of years required for a pixel to return to 80% of its pre-disturbance NBR (NBRpre) value. In this study, the Composite2Change (C2C) algorithm was used to generate a time series of gap-free, cloud-free Landsat surface reflectance composites (1985–2012), associated change metrics, and a spatially-explicit dataset of detected changes for an actively managed forest area in southern Finland (5.3 Mha). The overall accuracy of change detection, determined using independent validation data, was 89%. Areas of forest harvesting in 1991 were then used to evaluate the Y2R metric. Four alternative recovery scenarios were evaluated, representing variations in the spectral threshold used to define Y2R: 60%, 80%, and 100% of NBRpre, and a critical value of z (i.e. the year in which the pixel's NBR value is no longer significantly different from NBRpre). The Y2R for each scenario were classified into five groups: recovery within 17 years, and not recovered. Measures of forest structure (canopy height and cover) were obtained from ALS data. Benchmarks for height (>5 m) and canopy cover (>10%) were applied to each recovery scenario, and the percentage of pixels that attained both of these benchmarks for each recovery group, was determined for each Y2R scenario. Our results indicated that the Y2R metric using the 80% threshold provided the most realistic assessment of forest recovery: all pixels considered in our analysis were spectrally recovered within the analysis period, with 88.88% of recovered pixels attaining the benchmarks for both cover and height. Moreover, false positives (pixels that had recovered spectrally, but not structurally) and false negatives (pixels that had recovered structurally, but not spectrally) were minimized with the 80% threshold. This research demonstrates the efficacy of LTS-derived assessments of recovery, which can be spatially exhaustive and retrospective, providing important baseline data for forest monitoring.
  • Saukkonen, Anni (Helsingfors universitet, 2015)
    Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease affecting motor neurons. It finally leads to the malfunction of the respiratory muscles and death after 1-3 years of diagnosis. Sporadic cases of ALS cover 90-95% of all patients and familial 5-10% respectively. The onset of the disease is usually between age of 40 and 60 and the worldwide incidence is considered to be 1-2/100000. Currently discovered cerebral dopamine neurotrophic factor, CDNF, has showed neuroprotective effects on Parkinson's disease model. What is more, it is known that CDNF is expressed in the muscles of mice and one of its' main functions is to protect cells from ER-stress, one of the pathological mechanisms in ALS. Hence, it is rational to study the effects of CDNF in ALS mouse model. Treatment options are needed, since there is only one approved treatment for ALS, anti-glutaminergic rilutzole. The aim of this study was to find out whether CDNF shows neuroprotective effects in SOD1-mice e.g. by measuring the changes in motor function with different behavioral tests. More over, the distribution of CDNF after intrathecal ventricle injection was studied using immunohistochemical and radioactive labeling methods. The hypothesis was that CDNF is distributed through the cerebrospinal fluid into the spinal cord and muscles in the limbs and shows neuroprotective effects in this SOD1 mouse model.
  • Konovalova, Julia; Gerasymchuk, Dmytro; Parkkinen, Ilmari; Chmielarz, Piotr; Domanskyi, Andrii (2019)
    MicroRNAs are post-transcriptional regulators of gene expression, crucial for neuronal differentiation, survival, and activity. Age-related dysregulation of microRNA biogenesis increases neuronal vulnerability to cellular stress and may contribute to the development and progression of neurodegenerative diseases. All major neurodegenerative disorders are also associated with oxidative stress, which is widely recognized as a potential target for protective therapies. Albeit often considered separately, microRNA networks and oxidative stress are inextricably entwined in neurodegenerative processes. Oxidative stress affects expression levels of multiple microRNAs and, conversely, microRNAs regulate many genes involved in an oxidative stress response. Both oxidative stress and microRNA regulatory networks also influence other processes linked to neurodegeneration, such as mitochondrial dysfunction, deregulation of proteostasis, and increased neuroinflammation, which ultimately lead to neuronal death. Modulating the levels of a relatively small number of microRNAs may therefore alleviate pathological oxidative damage and have neuroprotective activity. Here, we review the role of individual microRNAs in oxidative stress and related pathways in four neurodegenerative conditions: Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) disease, and amyotrophic lateral sclerosis (ALS). We also discuss the problems associated with the use of oversimplified cellular models and highlight perspectives of studying microRNA regulation and oxidative stress in human stem cell-derived neurons.
  • Kokkoniemi, Samuli (Helsingfors universitet, 2012)
    Site index and site type are methods for describing a habitat’s highest annual production of tree (m3/ha/a). Site index is based on the growth of trees’ dominant height, and site type on the existence of plant communities in a habitat. This research examined whether site type can be estimated with site index derived by airborne laser scanning (ALS). ALS is a remote sensing method by which trees’ characteristics are predicted based on the height distribution and density values of laser pulses. Data were gathered from Syöte, Northern Ostrobothnia. Arbonaut Oy provided the ALS-data, and Metsähallitus provided age and habitat data of microstands. Site type, trees’ ages and dominant heights were also measured by field surveying. Experimental data from plots were generalized to microstand data. There were 208 experimental plots that were generalized to 39 microstands. Site indexes for experimental plots and microstands were calculated to index age 100 years with Vuokila and Väliaho’s (1980) growth models for dominant height and with Schumacher’s (1939) guide curve. Site indexes were converted to site types with Vuokila and Väliaho’s (1980) conversion diagram and then compared to site types of the field surveys. The accuracy of the site indexes was evaluated with an error matrix. Accuracy of age and dominant height was evaluated with a paired t-test. Variation of index aged dominant height inside a site type was examined with root mean square error (RMSE). The effect of the proportions of tree species on the site index was analyzed with a correlation coefficient. The percentage of properly classified site types was 57 % at best when using Schumacher’s (1939) guide curve and two site types (rich and poor). With Vuokila and Väliaho’s (1980) growth models for dominant height the best percentage of correctly classified site types was 46 %. The variation (RMSE) of index aged dominant height as an average in all site types was 3,2 m. The maximum variation of index aged dominant height in one site type was 6 m. This indicated that the dependency between site index and site type was poor with this data. The proportions of tree species did not have a significant effect on site index. Based on this study, predicting site types with ALS does not work. One problem is the absence of very rich site types. There are also many sources of error: SutiGIS’ (position knowledge system) age data, prescribed burning, possible fertilization of stands, and the problems of fitting site index and site type. Vuokila and Väliaho’s (1980) growth models for dominant height were made in the 1980s, so they do not acknowledge the increased growth of present-day trees. Site index cannot reliably predict the site type, but site index gives valuable extra information about the trees for example when evaluating the value of forest estates.
  • Genin, Emmanuelle C.; Bannwarth, Sylvie; Lespinasse, Francoise; Ortega-Vila, Bernardo; Fragaki, Konstantina; Itoh, Kie; Villa, Elodie; Lacas-Gervais, Sandra; Jokela, Manu; Auranen, Mari; Ylikallio, Emil; Mauri-Crouzet, Alessandra; Tyynismaa, Henna; Vihola, Anna; Auge, Gaelle; Cochaud, Charlotte; Sesaki, Hiromi; Ricci, Jean-Ehrland; Udd, Bjarne; Vives-Bauza, Cristofol; Paquis-Flucklinger, Veronique (2018)
    Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10(S59L) mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondria] dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10(G66V) allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10(S59L) allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease.