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3. Unfolded protein response markers Grp78 and eIF2alpha are upregulated with increasing alpha‐synuclein levels in Lewy body disease.

Author

Hrabos, Dominik, Poggiolini, Ilaria, Civitelli, Livia, Galli, Emilia, Esapa, Chris, Saarma, Mart, Lindholm, Päivi, and Parkkinen, Laura

Subjects
UNFOLDED protein response, PARKINSON'S disease, ENDOPLASMIC reticulum, SUBSTANTIA nigra, DENATURATION of proteins, ENTORHINAL cortex
Abstract

Aims: Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α‐synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α‐synuclein pathology in human post‐mortem brain tissue. Methods: We analysed brain tissue from 45 subjects—14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response‐related proteins (Grp78, eIF2α) and endoplasmic reticulum stress‐regulating neurotrophic factors (MANF, CDNF). Results: We showed that regional levels of two endoplasmic reticulum‐localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α‐synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α‐synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α‐synuclein levels. Conclusions: Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α‐synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α‐synuclein concentration and disease progression. [ABSTRACT FROM AUTHOR]

Published
2024
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4. MANF protein expression is upregulated in immune cells in the ischemic human brain and systemic recombinant MANF delivery in rat ischemic stroke model demonstrates anti-inflammatory effects

Author

Anttila, Jenni E., primary, Mattila, Olli S., additional, Liew, Hock-Kean, additional, Mätlik, Kert, additional, Mervaala, Eero, additional, Lindholm, Päivi, additional, Lindahl, Maria, additional, Lindsberg, Perttu J., additional, Tseng, Kuan-Yin, additional, and Airavaara, Mikko, additional

Published
2024
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9. CDNF rescues motor neurons in models of amyotrophic lateral sclerosis by targeting endoplasmic reticulum stress

Author

De Lorenzo, Francesca, primary, Lüningschrör, Patrick, additional, Nam, Jinhan, additional, Beckett, Liam, additional, Pilotto, Federica, additional, Galli, Emilia, additional, Lindholm, Päivi, additional, Rüdt von Collenberg, Cora, additional, Tii Mungwa, Simon, additional, Jablonka, Sibylle, additional, Kauder, Julia, additional, Thau-Habermann, Nadine, additional, Petri, Susanne, additional, Lindholm, Dan, additional, Saxena, Smita, additional, Sendtner, Michael, additional, Saarma, Mart, additional, and Voutilainen, Merja H, additional

Published
2023
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11. CDNF rescues motor neurons in models of amyotrophic lateral sclerosis by targeting endoplasmic reticulum stress.

Author

Lorenzo, Francesca De, Lüningschrör, Patrick, Nam, Jinhan, Beckett, Liam, Pilotto, Federica, Galli, Emilia, Lindholm, Päivi, Collenberg, Cora Rüdt von, Mungwa, Simon Tii, Jablonka, Sibylle, Kauder, Julia, Thau-Habermann, Nadine, Petri, Susanne, Lindholm, Dan, Saxena, Smita, Sendtner, Michael, Saarma, Mart, and Voutilainen, Merja H

Subjects
AMYOTROPHIC lateral sclerosis, MOTOR neurons, ENDOPLASMIC reticulum, UNFOLDED protein response, SPINAL cord
Abstract

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects motor neurons in the spinal cord, brainstem and motor cortex, leading to paralysis and eventually to death within 3–5 years of symptom onset. To date, no cure or effective therapy is available. The role of chronic endoplasmic reticulum stress in the pathophysiology of amyotrophic lateral sclerosis, as well as a potential drug target, has received increasing attention. Here, we investigated the mode of action and therapeutic effect of the endoplasmic reticulum-resident protein cerebral dopamine neurotrophic factor in three preclinical models of amyotrophic lateral sclerosis, exhibiting different disease development and aetiology: (i) the conditional choline acetyltransferase-tTA/TRE-hTDP43-M337V rat model previously described; (ii) the widely used SOD1-G93A mouse model; and (iii) a novel slow-progressive TDP43-M337V mouse model. To specifically analyse the endoplasmic reticulum stress response in motor neurons, we used three main methods: (i) primary cultures of motor neurons derived from embryonic Day 13 embryos; (ii) immunohistochemical analyses of spinal cord sections with choline acetyltransferase as spinal motor neuron marker; and (iii) quantitative polymerase chain reaction analyses of lumbar motor neurons isolated via laser microdissection. We show that intracerebroventricular administration of cerebral dopamine neurotrophic factor significantly halts the progression of the disease and improves motor behaviour in TDP43-M337V and SOD1-G93A rodent models of amyotrophic lateral sclerosis. Cerebral dopamine neurotrophic factor rescues motor neurons in vitro and in vivo from endoplasmic reticulum stress-associated cell death and its beneficial effect is independent of genetic disease aetiology. Notably, cerebral dopamine neurotrophic factor regulates the unfolded protein response initiated by transducers IRE1α, PERK and ATF6, thereby enhancing motor neuron survival. Thus, cerebral dopamine neurotrophic factor holds great promise for the design of new rational treatments for amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

Published
2023
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12. MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α

Author

Kovaleva, Vera, primary, Yu, Li-Ying, additional, Ivanova, Larisa, additional, Shpironok, Olesya, additional, Nam, Jinhan, additional, Eesmaa, Ave, additional, Kumpula, Esa-Pekka, additional, Sakson, Sven, additional, Toots, Urve, additional, Ustav, Mart, additional, Huiskonen, Juha T., additional, Voutilainen, Merja H., additional, Lindholm, Päivi, additional, Karelson, Mati, additional, and Saarma, Mart, additional

Published
2023
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20. Cover Image, Volume 528, Issue 14

Author

Chalazonitis, Alcmène, primary, Li, ZhiShan, additional, Pham, Tuan D., additional, Chen, Jason, additional, Rao, Meenakshi, additional, Lindholm, Päivi, additional, Saarma, Mart, additional, Lindahl, Maria, additional, and Gershon, Michael D., additional

Published
2020
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21. CDNF rescues motor neurons in three animal models of ALS by targeting ER stress

Author

De Lorenzo, Francesca, primary, Lüningschrör, Patrick, additional, Nam, Jinhan, additional, Pilotto, Federica, additional, Galli, Emilia, additional, Lindholm, Päivi, additional, von Collenberg, Cora Rüdt, additional, Mungwa, Simon Tii, additional, Jablonka, Sibylle, additional, Kauder, Julia, additional, Petri, Susanne, additional, Lindholm, Dan, additional, Saxena, Smita, additional, Sendtner, Michael, additional, Saarma, Mart, additional, and Voutilainen, Merja H., additional

Published
2020
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27. Brain structural deficits and working memory fMRI dysfunction in young adults who were diagnosed with ADHD in adolescence

Author

Roman-Urrestarazu, Andres, Lindholm, Päivi, Moilanen, Irma, Kiviniemi, Vesa, Miettunen, Jouko, Jääskeläinen, Erika, Mäki, Pirjo, Hurtig, Tuula, Ebeling, Hanna, Barnett, Jennifer H., Nikkinen, Juha, Suckling, John, Jones, Peter B., Veijola, Juha, Murray, Graham K., Suckling, John [0000-0002-5098-1527], Jones, Peter [0000-0002-0387-880X], Murray, Graham [0000-0001-8296-1742], and Apollo - University of Cambridge Repository

Subjects
Male, Memory Disorders, Adolescent, Brain, Original Contribution, behavioral disciplines and activities, Magnetic Resonance Imaging, Cohort Studies, Psychiatry and Mental health, Neuroanatomy, Young Adult, Memory, Short-Term, Memory, Attention Deficit Disorder with Hyperactivity, mental disorders, ADHD, Hyperkinetic, Humans, Female, Pediatrics, Perinatology, and Child Health, VBM, Finland, Photic Stimulation, Psychomotor Performance, MRI
Abstract

When adolescents with ADHD enter adulthood, some no longer meet disorder diagnostic criteria but it is unknown if biological and cognitive abnorma lities persist. We tested the hypothesis that people diagnosed with ADHD during adolescence present residual brain abnormalities both in brain structure and in working memory brain function. 83 young adults (aged 20-24 years) from the Northern Finland 1986 Birth Cohort were classified as diagnosed with ADHD in adolescence (adolescence ADHD, n = 49) or a control group (n = 34). Only one patient had received medication for ADHD. T1-weighted brain scans were acquired and processed in a voxel-based analysis using permutation-based statistics. A sub-sample of both groups (ADHD, n = 21; controls n = 23) also performed a Sternberg working memory task whilst acquiring fMRI data. Areas of structural difference were used as a region of interest to evaluate the implications that structural abnormalities found in the ADHD group might have on working memory function. There was lower grey matter volume bilaterally in adolescence ADHD participants in the caudate (p < 0.05 FWE corrected across the whole brain) at age 20-24. Working memory was poorer in adolescence ADHD participants, with associated failure to show normal load-dependent caudate activation. Young adults diagnosed with ADHD in adolescence have structural and functional deficits in the caudate associated with abnormal working memory function. These findings are not secondary to stimulant treatment, and emphasise the importance of taking a wider perspective on ADHD outcomes than simply whether or not a particular patient meets diagnostic criteria at any given point in time.

Published
2015

28. Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes

Author

Balboa, Diego, primary, Saarimäki-Vire, Jonna, additional, Borshagovski, Daniel, additional, Survila, Mantas, additional, Lindholm, Päivi, additional, Galli, Emilia, additional, Eurola, Solja, additional, Ustinov, Jarkko, additional, Grym, Heli, additional, Huopio, Hanna, additional, Partanen, Juha, additional, Wartiovaara, Kirmo, additional, and Otonkoski, Timo, additional

Published
2018
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29. Author response: Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes

Author

Balboa, Diego, primary, Saarimäki-Vire, Jonna, additional, Borshagovski, Daniel, additional, Survila, Mantas, additional, Lindholm, Päivi, additional, Galli, Emilia, additional, Eurola, Solja, additional, Ustinov, Jarkko, additional, Grym, Heli, additional, Huopio, Hanna, additional, Partanen, Juha, additional, Wartiovaara, Kirmo, additional, and Otonkoski, Timo, additional

Published
2018
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30. Poststroke delivery of MANF promotes functional recovery in rats

Author

Mätlik, Kert, primary, Anttila, Jenni E., additional, Kuan-Yin, Tseng, additional, Smolander, Olli-Pekka, additional, Pakarinen, Emmi, additional, Lehtonen, Leevi, additional, Abo-Ramadan, Usama, additional, Lindholm, Päivi, additional, Zheng, Congjun, additional, Harvey, Brandon, additional, Arumäe, Urmas, additional, Lindahl, Maria, additional, and Airavaara, Mikko, additional

Published
2018
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33. Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action

Author

Voutilainen, Merja H., primary, De Lorenzo, Francesca, additional, Stepanova, Polina, additional, Bäck, Susanne, additional, Yu, Li-Ying, additional, Lindholm, Päivi, additional, Pörsti, Eeva, additional, Saarma, Mart, additional, Männistö, Pekka T., additional, and Tuominen, Raimo K., additional

Published
2017
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35. Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster

Author

University of Helsinki, Institute of Biotechnology, University of Helsinki, Institute of Biotechnology (-2009), University of Helsinki, Department of Biosciences, Lindström, Riitta, Lindholm, Päivi, Kallijärvi, Jukka, Palgi, Mari, Saarma, Mart, Heino, Tapio I., University of Helsinki, Institute of Biotechnology, University of Helsinki, Institute of Biotechnology (-2009), University of Helsinki, Department of Biosciences, Lindström, Riitta, Lindholm, Päivi, Kallijärvi, Jukka, Palgi, Mari, Saarma, Mart, and Heino, Tapio I.

Abstract

Disturbances in the homeostasis of endoplasmic reticulum (ER) referred to as ER stress is involved in a variety of human diseases. ER stress activates unfolded protein response (UPR), a cellular mechanism the purpose of which is to restore ER homeostasis. Previous studies show that Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is an important novel component in the regulation of UPR. In vertebrates, MANF is upregulated by ER stress and protects cells against ER stress-induced cell death. Biochemical studies have revealed an interaction between mammalian MANF and GRP78, the major ER chaperone promoting protein folding. In this study we discovered that the upregulation of MANF expression in response to drug-induced ER stress is conserved between Drosophila and mammals. Additionally, by using a genetic in vivo approach we found genetic interactions between Drosophila Manf and genes encoding for Drosophila homologues of GRP78, PERK and XBP1, the key components of UPR. Our data suggest a role for Manf in the regulation of Drosophila UPR.

Published
2016

36. Comparative analysis of the effects of neurotrophic factors CDNF and GDNF in a nonhuman primate model of Parkinson’s disease

Author

Garea-Rodríguez, Enrique, Eesmaa, Ave, Lindholm, Päivi K, Schlumbohm, Christina, König, Jessica, Meller, Birgit, Krieglstein, Kerstin, Helms, Gunther, Saarma, Mart, Fuchs, Eberhard, Garea-Rodríguez, Enrique, Eesmaa, Ave, Lindholm, Päivi K, Schlumbohm, Christina, König, Jessica, Meller, Birgit, Krieglstein, Kerstin, Helms, Gunther, Saarma, Mart, and Fuchs, Eberhard

Abstract

Cerebral dopamine neurotrophic factor (CDNF) belongs to a newly discovered family of evolutionarily conserved neurotrophic factors.We demonstrate for the first time a therapeutic effect of CDNF in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson’s disease in marmoset monkeys. Furthermore, we tested the impact of high chronic doses of human recombinant CDNF on unlesionedmonkeys and analyzed the amino acid sequence ofmarmoset CDNF. The severity of 6-OHDA lesions and treatment effects weremonitored in vivo using 123I-FP-CIT (DaTSCAN) SPECT. Quantitative analysis of 123I-FP-CIT SPECT showed a significant increase of dopamine transporter binding activity in lesioned animals treated with CDNF. Glial cell line-derived neurotrophic factor (GDNF), a well-characterized and potent neurotrophic factor for dopamine neurons, served as a control in a parallel comparison with CDNF. By contrast with CDNF, only single animals responded to the treatment with GDNF, but no statistical difference was observed in the GDNF group. However, increased numbers of tyrosine hydroxylase immunoreactive neurons, observed within the lesioned caudate nucleus of GDNF-treated animals, indicate a strong bioactive potential of GDNF.

Published
2016

40. DTI abnormalities in adults with past history of attention deficit hyperactivity disorder: a tract-based spatial statistics study

Author

Bode, Michaela K, primary, Lindholm, Päivi, additional, Kiviniemi, Vesa, additional, Moilanen, Irma, additional, Ebeling, Hanna, additional, Veijola, Juha, additional, Miettunen, Jouko, additional, Hurtig, Tuula, additional, Nordström, Tanja, additional, Starck, Tuomo, additional, Remes, Jukka, additional, Tervonen, Osmo, additional, and Nikkinen, Juha, additional

Published
2015
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