Browsing by Subject "Parkinson's disease"

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  • Ardashov, Oleg V.; Pavlova, Alla V.; Mahato, Arun Kumar; Sidorova, Yulia; Morozova, Ekaterina A.; Korchagina, Dina V.; Salnikov, Georgi E.; Genaev, Alexander M.; Patrusheva, Oksana S.; Li-Zhulanov, Nikolay S.; Tolstikova, Tat'yana G.; Volcho, Konstantin P.; Salakhutdinov, Nariman. F. (2019)
    We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 alleviates motor manifestations of Parkinson's disease in animal models. In the present study, we designed and synthesized monoepoxides of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 and evaluated their biological activity in the MPTP mouse model of Parkinson's disease. We also assessed the ability of these compounds to penetrate the blood-brain barrier (BBB). According to these data, we chose epoxide 4, which potently restored the locomotor activity in MPTP-treated mice and efficiently penetrated the BBB, to further explore its potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons against toxin-induced degeneration, and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal origin. Meanwhile, neither the survival-promoting effect nor MAPK activation was observed in non-neuronal cells treated with epoxide 4. In the MPTP mouse model of Parkinson's disease, compound 4 increased the density of dopamine neuron fibers in the striatum, which can highlight its potential to stimulate striatal reinnervation and thus halt disease progression. Taken together, these data indicate that epoxide 4 can be a promising compound for further development, not only as a symptomatic but also as a neuroprotective and neurorestorative drug for Parkinson's disease.
  • Albert, Katrina; Voutilainen, Merja H.; Domanskyi, Andrii; Airavaara, Mikko (2017)
    Gene delivery using adeno-associated virus (AAV) vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson's disease. AAV-based gene targeting to the projection area of these neurons in the striatum has been studied extensively to induce the production of neurotrophic factors for disease-modifying therapies for Parkinson's disease. Much less emphasis has been put on AAV-based gene therapy targeting dopamine neurons in substantia nigra. We will review the literature related to targeting striatum and/or substantia nigra dopamine neurons using AAVs in order to express neuroprotective and neurorestorative molecules, as well as produce animal disease models of Parkinson's disease. We discuss difficulties in targeting substantia nigra dopamine neurons and their vulnerability to stress in general. Therefore, choosing a proper control for experimental work is not trivial. Since the axons along the nigrostriatal tract are the first to degenerate in Parkinson's disease, the location to deliver the therapy must be carefully considered. We also review studies using AAV--synuclein (-syn) to target substantia nigra dopamine neurons to produce an -syn overexpression disease model in rats. Though these studies are able to produce mild dopamine system degeneration in the striatum and substantia nigra and some behavioural effects, there are studies pointing to the toxicity of AAV-carrying green fluorescent protein (GFP), which is often used as a control. Therefore, we discuss the potential difficulties in overexpressing proteins in general in the substantia nigra.
  • Aaltonen, Linda (Helsingfors universitet, 2015)
    Parkinson's disease is a neurodegenerative disease where the nigrostriatal dopaminergic cells die gradually causing severe motor symptoms. Current treatment of the disease relieves the symptoms but does not affect the progression of the disease, nor does it have a neuroprotective effect. The most important drug for the treatment of Parkinson's disease is L-dopa, the precursor of dopamine. With long-term use, L-dopa loses its efficacy and patients start to get adverse effects. The most significant adverse effects are abnormal involuntary movements called dyskinesias. In the literature review of this thesis Parkinson's disease and its treatment is briefly described. Review focuses on the description of the brain cholinergic and histaminergic systems and their receptors along with the available studies about cholinergic and histaminergic neurotransmission in Parkinson's disease 6-hydroxydopamine (6-OHDA) rodent model. The experimental part of this thesis consisted of two different set of experiments and in both of these the dopamine neurons were destroyed unilaterally by injecting 6-OHDA into the striatum. The aim of the first experiment was to examine histamine H3-receptor antagonist JNJ-39220675 and α7-nicotinic receptor agonist PHA-543613, and their combination therapy effects on motor function and the concentrations of striatal neurotransmitters in hemiparkinsonian mice. Effects on motor function were studied two and four weeks after the 6-OHDA injection with cylinder test, the D-amphetamine-induced rotations, and the inverted grid test. After behavioral tests, mice were sacrificed and striatal neurotransmitter concentrations were determinated by HPLC. The aim of the second experiment was to examine if nicotine can relieve L-dopa-induced dyskinesias. In this experiment 6-OHDA was injected at two sites into the striatum, which was intended to produce more extensive destruction of dopaminergic neurons than in the first experiment. The extent of the lesion by 6-OHDA was verified before starting chronic L-dopa treatments with cylinder test. One month after the 6-OHDA injection, five mice were sacrificed and their striatum and substantia nigra sections were measured for destruction of dopaminergic neurons by immunohistochemical TH-staining. Chronic L-dopa treatment with benserazide was started 49‚àí63 days after the 6-OHDA injection. At the same time, mice were divided into two groups. Half of them got normal drinking water and half got nicotine water. During the chronic L-dopa treatment, development of dyskinesias was observed once a week by video tracking. The cylinder test was also done once again after starting the L-dopa treatment. In the first experiment, H3-receptor antagonist JNJ-39220675 showed promising results in improving motor function. Mice used the impaired (contralateral) paw more in the cylinder test and rotated less to the ipsilateral side in the D-amphetamine-induced rotation test than control animals two weeks after the 6-OHDA injection. Combination therapy also reduced the ipsilateral rotations but in the cylinder test it had no effect two weeks after 6-OHDA injection. Because the asymmetry in behavioural tests were caused by destroying dopaminergic neurons, balancing of the motor skills can result from decreased levels of dopamine in the intact side or from increased dopamine levels or stronger dopaminergic postsynaptic transmission in the lesion side. The results four weeks after 6-OHDA injection are not reliable because the striatal samples showed that dopamine concentrations in the lesion side were very close to that of the intact side indicating recovery from the lesion. In the second experiment, mice developed dyskinesias which were decreased with nicotine treatment. Mice also used the contralateral side paw less indicative of loss of dopamine neurons. In agreement, TH-immunostaining confirmed significant loss of TH-positive neurons. Based on these findings, the 6-OHDA injection site, the selected drug doses, and the experimental design seem to fit the evaluation of dyskinesias. The occurrence of dyskinesias and nicotine's effect on them was seen strongest in the body movements. Dyskinesias in forelimbs were minor, but the nicotine treatment decreased them also.
  • Annanmaki, Tua; Palmu, Kirsi; Murros, Kari; Partanen, Juhani (2017)
    The diagnosis of cognitive impairment and dementia often occurring with Parkinson's disease (PD) is still based on the clinical picture and neuropsychological examination. Ancillary methods to detect cognitive decline in these patients are, therefore, needed. Alterations in the latencies and amplitudes of evoked response potential (ERP) components N100 and P200 have been described in PD. Due to limited number of studies their relation to cognitive deficits in PD remains obscure. The present study was designed to examine if alterations in the N100- and P200-potentials associate with neuropsychological impairment in PD. EEG-ERP was conducted to 18 PD patients and 24 healthy controls. The patients underwent a thorough neuropsychological evaluation. The controls were screened for cognitive impairment with Consortium to Establish Alzheimer's disease (CERAD)-testing and a normal result were required to be included in the study. The N100-latency was prolonged in the patients compared to the controls (p = 0.05). In the patients, the N100 latency correlated significantly with a visual working memory task (p = 0.01). Also N100 latency was prolonged and N100 amplitude habituation diminished in the patients achieving poorly in this task. We conclude that prolonged N100-latency and diminished amplitude habituation associate with visual working memory impairment in PD.
  • Oksanen, Minna; Lehtonen, Sarka; Jaronen, Merja; Goldsteins, Gundars; Hämäläinen, Riikka H.; Koistinaho, Jari (2019)
    Astrocytes are the most abundant cell type in the brain. They were long considered only as passive support for neuronal cells. However, recent data have revealed many active roles for these cells both in maintenance of the normal physiological homeostasis in the brain as well as in neurodegeneration and disease. Moreover, human astrocytes have been found to be much more complex than their rodent counterparts, and to date, astrocytes are known to actively participate in a multitude of processes such as neurotransmitter uptake and recycling, gliotransmitter release, neuroenergetics, inflammation, modulation of synaptic activity, ionic balance, maintenance of the blood–brain barrier, and many other crucial functions of the brain. This review focuses on the role of astrocytes in human neurodegenerative disease and the potential of the novel stem cell-based platforms in modeling astrocytic functions in health and in disease.
  • Leino, Sakari; Koski, Sini K.; Hänninen, Raisa; Tapanainen, Tuukka; Rannanpää, Saara; Salminen, Outi (2018)
    Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.
  • Jaakkola, Elina; Joutsa, Juho; Makinen, Elina; Noponen, Tommi; Pitkonen, Miia; Levo, Reeta; Mertsalmi, Tuomas; Scheperjans, Filip; Kaasinen, Valtteri (2019)
    Background: Non-motor symptoms (NMSs) are clearly more prevalent in Parkinson's disease (PD) patients compared to healthy individuals. However, NMSs are also common in the elderly and other neurological conditions, and thus, it is not known whether NMSs could be used to differentiate PD from parkinsonism/tremor without dopamine deficiency. Methods: We prospectively evaluated NMSs immediately before brain dopamine transporter (DAT) [I-123]FP-CIT SPECT scanning in 193 patients with unclear parkinsonism/tremor. According to the clinical follow-up and imaging results, 84 patients had PD. NMSs and their correlations with striatal DAT binding were investigated in PD patients and in parkinsonism/tremor patients with normal dopamine function. Results: Total NMS burden, anxiety or depression did not differ between PD patients and patients with normal DAT binding. DAT-normal patients reported more perception-related (p = 0.045) and attention/memory-related NMSs than PD patients (p <0.001). Total NMS score did not correlate with striatal DAT binding in either group. Conclusions: In clinically uncertain cases, the total NMS burden cannot be used as a tool in distinguishing PD patients from patients with non-dopaminergic parkinsonism/tremor. Clinical screening of NMSs appears equally important in all patients with parkinsonism.
  • Lindholm, Dan; Pham, Dan D.; Cascone, Annunziata; Eriksson, Ove; Wennerberg, Krister; Saarma, Mart (2016)
    Parkinson's disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as alpha-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia have shown promising neuroprotective effects in cell and animal models of PD. This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors. Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors. Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients.
  • Almeida, Sérgio (Helsingfors universitet, 2016)
    Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) form a novel neurotrophic factor family due to their unique structure and different mode of action when compared to classical neurotrophic factors. CDNF and MANF have shown to protect dopaminergic neurons in Parkinson's disease animal models and therefore they are considered potential therapy agents. However, their target molecules, i.e., putative receptor(s) and signalling pathways are still unknown. 78 kDa glucose-regulated protein (GRP78) member of the heat shock protein (HSP) family is a major chaperone that under Endoplasmic Reticulum (ER) stress conditions is up-regulated and prevents protein aggregation as well as facilitates degradation of misfolded proteins. It locates mainly in the ER but location can change in different conditions. In cancer research, GRP78 has been found highly expressed on the surface of cancer cells where it regulates critical oncogenic signalling pathways. For example, it was recently shown that Par-4 (Prostate apoptosis response-4) induces apoptosis via activation of caspase-3 by binding to GRP78, expressed at the surface of cancer cells. GRP78 has been shown capable of relocating extracellularly also in neurons. Especially, it was recently shown that accumulating extracellular α-synuclein induces an increase in surface-exposed GRP78 in cultured neurons. α-synuclein interacts with cell surface GRP78 and activates a signalling cascade affecting the morphology and dynamics of actin cytoskeleton. Our group has recent, yet unpublished data suggesting that CDNF and MANF interact with GRP78 protein. The emerging role for GRP78 also in the neurodegeneration requests further investigation on its possible interaction with CDNF and MANF and on the biological meaning of that interaction. In order to test whether CDNF and MANF would interact with cell surface GRP78 and possibly compete with par-4 for the binding and in this way prevent apoptosis, we built a plasmid that would guide the expression and extracellular localization of GRP78 in the transfected cells. We transfected HEK293 cells with this plasmid and incubated them for 24h with two concentrations of par-4. We could see a trend of increasing apoptosis in PAR-4 –treated cells, but this was not enhanced in the cells expressing GRP78 extracellularly, as we had hypothesised. Thus we did not continue further with testing CDNF and MANF on this setting. Transfected HEK293 cells were incubated with alkaline phosphatase tagged MANF or CDNF (AP-MANF or AP-CDNF) and using the alkaline phosphatase substrate pNitrophenylphosphate (pNPP), we were able to study the binding between GRP78 and CDNF and MANF. Even though we could not prove the cell surface GRP78 interaction with MANF with this method, we show a high affinity binding between cell surface GRP78 and CDNF when transfected cells are incubated with different concentrations of AP-CDNF.
  • Albert, Katrina; Renko, Juho-Matti; Mätlik, Kert; Airavaara, Mikko; Voutilainen, Merja H. (2019)
    Cerebral dopamine neurotrophic factor (CDNF) has shown therapeutic potential in rodent and non-human primate models of Parkinson's disease by protecting the dopamine neurons from degeneration and even restoring their phenotype and function. Previously, neurorestorative efficacy of CDNF in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease as well as diffusion of the protein in the striatum (STR) has been demonstrated and studied. Here, experiments were performed to characterize the diffusion and transport of supra-nigral CDNF in non-lesioned rats. We injected recombinant human CDNF to the substantia nigra (SN) of naive male Wistar rats and analyzed the brains 2, 6, and 24 h after injections. We performed immunohistochemical stainings using an antibody specific to human CDNF and radioactivity measurements after injecting iodinated CDNF. Unlike the previously reported striatonigral retrograde transport seen after striatal injection, active anterograde transport of CDNF to the STR could not be detected after nigral injection. There was, however, clear diffusion of CDNF to the brain areas surrounding the SN, and CDNF colocalized with tyrosine hydroxylase (TH)-positive neurons. Overall, our results provide insight on how CDNF injected to the SN may act in this region of the brain.
  • Lindahl, Maria; Chalazonitis, Alcmene; Palm, Erik; Pakarinen, Emmi; Danilova, Tatiana; Pham, Tuan D.; Setlik, Wanda; Rao, Meenakshi; Voikar, Vootele; Huotari, Jatta; Kopra, Jaakko; Andressoo, Jaan-Olle; Piepponen, Petteri T.; Airavaara, Mikko; Panhelainen, Anne; Gershon, Michael D.; Saarma, Mart (2020)
    Cerebral dopamine neurotrophic factor (CDNF) is neuroprotective for nigrostriatal dopamine neurons and restores dopaminergic function in animal models of Parkinson's disease (PD). To understand the role of CDNF in mammals, we generated CDNF knockout mice (Cdnf(-/-)), which are viable, fertile, and have a normal life-span. Surprisingly, an age-dependent loss of enteric neurons occurs selectively in the submucosal but not in the myenteric plexus. This neuronal loss is a consequence not of increased apoptosis but of neurodegeneration and autophagy. Quantitatively, the neurodegeneration and autophagy found in the submucosal plexus in duodenum, ileum and colon of the Cdnf(-/-) mouse are much greater than in those of Cdnf(+/+) mice. The selective vulnerability of submucosal neurons to the absence of CDNF is reminiscent of the tendency of pathological abnormalities to occur in the submucosal plexus in biopsies of patients with PD. In contrast, the number of substantia nigra dopamine neurons and dopamine and its metabolite concentrations in the striatum are unaltered in Cdnf(-/-) mice; however, there is an age-dependent deficit in the function of the dopamine system in Cdnf(-/-) male mice analyzed. This is observed as D-amphetamine-induced hyperactivity, aberrant dopamine transporter function, and as increased D-amphetamine-induced dopamine release demonstrating that dopaminergic axon terminal function in the striatum of the Cdnf(-/-) mouse brain is altered. The deficiencies of Cdnf(-/-) mice, therefore, are reminiscent of those seen in early stages of Parkinson's disease.
  • Brodski, Claude; Blaess, Sandra; Partanen, Juha; Prakash, Nilima (2019)
    Dopamine-synthesizing neurons located in the mammalian ventral midbrain are at the center stage of biomedical research due to their involvement in severe human neuropsychiatric and neurodegenerative disorders, most prominently Parkinson's Disease (PD). The induction of midbrain dopaminergic (mDA) neurons depends on two important signaling centers of the mammalian embryo: the ventral midline or floor plate (FP) of the neural tube, and the isthmic organizer (IsO) at the mid-/hindbrain boundary (MHB). Cells located within and close to the FP secrete sonic hedgehog (SHH), and members of the wingless-type MMTV integration site family (WNT1/5A), as well as bone morphogenetic protein (BMP) family. The IsO cells secrete WNT1 and the fibroblast growth factor 8 (FGF8). Accordingly, the FGF8, SHH, WNT, and BMP signaling pathways play crucial roles during the development of the mDA neurons in the mammalian embryo. Moreover, these morphogens are essential for the generation of stem cell-derived mDA neurons, which are critical for the modeling, drug screening, and cell replacement therapy of PD. This review summarizes our current knowledge about the functions and crosstalk of these signaling pathways in mammalian mDA neuron development in vivo and their applications in stem cell-based paradigms for the efficient derivation of these neurons in vitro.
  • Kuusimäki, Tomi; Korpela, Jaana; Pekkonen, Eero; Martikainen, Mika H.; Antonini, Angelo; Kaasinen, Valtteri (2020)
    Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD) patients with motor fluctuations and dyskinesias. The key DBS efficacy studies were performed in PD patients with unknown genotypes; however, given the estimated monogenic mutation prevalence of approximately 5-10%, most commonly LRRK2, PRKN, PINK1 and SNCA, and risk-increasing genetic factors such as GBA, proper characterization is becoming increasingly relevant. We performed a systematic review of 46 studies that reported DBS effects in 221 genetic PD patients. The results suggest that monogenic PD patients have variable DBS benefit depending on the mutated gene. Outcome appears excellent in patients with the most common LRRK2 mutation, p.G2019S, and good in patients with PRKN mutations but poor in patients with the more rare LRRK2 p.R1441G mutation. The overall benefit of DBS in SNCA, GBA and LRRK2 p.T2031S mutations may be compromised due to rapid progression of cognitive and neuropsychiatric symptoms. In the presence of other mutations, the motor changes in DBS-treated monogenic PD patients appear comparable to those of the general PD population.
  • Runeberg-Roos, Pia; Piccinini, Elisa; Penttinen, Anna-Maija; Matlik, Kert; Heikkinen, Hanna; Kuure, Satu; Bespalov, Maxim M.; Peranen, Johan; Garea-Rodriguez, Enrique; Fuchs, Eberhard; Airavaara, Mikko; Kalkkinen, Nisse; Penn, Richard; Saarma, Mart (2016)
    In Parkinson's disease midbrain dopaminergic neurons degenerate and die. Oral medications and deep brain stimulation can relieve the initial symptoms, but the disease continues to progress. Growth factors that might support the survival, enhance the activity, or even regenerate degenerating dopamine neurons have been tried with mixed results in patients. As growth factors do not pass the blood-brain barrier, they have to be delivered intracranially. Therefore their efficient diffusion in brain tissue is of crucial importance. To improve the diffusion of the growth factor neurturin (NRTN), we modified its capacity to attach to heparan sulfates in the extracellular matrix. We present four new, biologically fully active variants with reduced heparin binding. Two of these variants are more stable than WT NRTN in vitro and diffuse better in rat brains. We also show that one of the NRTN variants diffuses better than its close homolog GDNF in monkey brains. The variant with the highest stability and widest diffusion regenerates dopamine fibers and improves the conditions of rats in a 6-hydroxydopamine model of Parkinson's disease more potently than GDNF, which previously showed modest efficacy in clinical trials. The new NRTN variants may help solve the major problem of inadequate distribution of NRTN in human brain tissue. (C) 2016 Elsevier Inc. All rights reserved.
  • Hlushchuk, Irena; Ruskoaho, Heikki; Domanskyi, Andrii; Airavaara, Mikko; Välimäki, Mika J. (2021)
    Neurodegenerative diseases are associated with failed proteostasis and accumulation of insoluble protein aggregates that compromise neuronal function and survival. In Parkinson's disease, a major pathological finding is Lewy bodies and neurites that are mainly composed of phosphorylated and aggregated alpha-synuclein and fragments of organelle membranes. Here, we analyzed a series of selective inhibitors acting on multidomain proteins CBP and p300 that contain both lysine acetyltransferase and bromodomains and are responsible for the recognition and enzymatic modification of lysine residues. By using high-affinity inhibitors, A-485, GNE-049, and SGC-CBP30, we explored the role of two closely related proteins, CBP and p300, as promising targets for selective attenuation of alpha-synuclein aggregation. Our data show that selective CBP/p300 inhibitors may alter the course of pathological alpha-synuclein accumulation in primary mouse embryonic dopaminergic neurons. Hence, drug-like CBP/p300 inhibitors provide an effective approach for the development of high-affinity drug candidates preventing alpha-synuclein aggregation via systemic administration.
  • Leino, Sakari; Kohtala, Samuel; Rantamäki, Tomi; Koski, Sini K.; Rannanpää, Saara; Salminen, Outi (2018)
    BackgroundThe treatment of Parkinson's disease is often complicated by levodopa-induced dyskinesia (LID). Nicotinic acetylcholine receptor agonists can alleviate LID in animal models but may be less effective in conditions of severe dopaminergic denervation. While the mechanisms of LID remain incompletely understood, elevated corticostriatal levels of the brain-derived neurotrophic factor (BDNF) have been suggested to play a role. Here, female mice with near-total unilateral 6-hydroxydopamine-induced nigrostriatal lesions were chronically treated with levodopa, and the effects of the 7 nicotinic receptor partial agonist AZD0328 and nicotine on LID were assessed. At the end of the experiment, BDNF protein levels in the prefrontal cortex and striatum were measured.ResultsFive-day treatments with three escalating doses of AZD0328 and a 10-week treatment with nicotine failed to alleviate LID. BDNF levels in the lesioned striatum correlated positively with LID severity, but no evidence was found for a levodopa-induced elevation of corticostriatal BDNF in the lesioned hemisphere. The nicotine treatment decreased BDNF levels in the prefrontal cortex but had no effect on striatal BDNF.ConclusionsThe findings suggest that treatment of LID with nicotinic agonists may lose its effectiveness as the disease progresses, represent further evidence for a role for BDNF in LID, and expand previous knowledge on the effects of long-term nicotine treatment on BDNF.
  • Lei, Jing; Ye, Gang; Pertovaara, Antti; You, Hao-Jun (2020)
    Here we investigated variations of endogenous descending modulation of nociception and therapeutic effects of intramuscular (i.m.) heating-needle stimulation in early stage of Parkinson's disease (PD) induced by unilateral microinjection of 3.5 mu l of 2.5 mu g/mu l 6-hydroxydopamine into the rat striatum. Paw withdrawal reflexes to noxious mechanical and heat stimuli in PD rats with and without exposure to i.m. 5.8% saline induced muscle nociception were evaluated. Experimental PD had no influence on mechanical or heat sensitivity in the baseline condition, whereas descending facilitation was stronger and descending inhibition was weaker in PD rats than vehicle-treated or naive rats during muscle nociception (P <0.05). Striatal administration of 5 mu g of dopamine failed to reverse the PD-associated changes in descending facilitation or inhibition, whereas dopamine in the thalamic mediodorsal (MD) nucleus and ventromedial (VM) nucleus significantly decreased the increase in descending facilitation and reversed the attenuation in descending inhibition, respectively (P <0.05). I.m. 43 degrees C of heating-needle stimulation had no effects on the enhanced descending facilitation in PD rats, but it markedly increased descending inhibition and reversed the increase in the number of apomorphine-induced body rotations (P <0.05), which effects were dose-dependently attenuated by raclopride, a dopamine 2 receptor antagonist, in the thalamic VM nucleus (P <0.05). The results indicate that the early-stage PD is associated with enhanced descending facilitation and weakened descending inhibition. From clinical perspective, 43 degrees C heat therapeutic regime promises to selectively enhance descending inhibition that is accompanied by improvement of motor dysfunction in PD. (c) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Kovaleva, Vera; Saarma, Mart (2021)
    Parkinson's disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborization and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2+ dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2+ homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signaling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in an animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical animal models of PD. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.
  • Barker, Roger A.; Björklund, Anders; Gash, Don M.; Whone, Alan; Laar, Amber Van; Kordower, Jeffrey H.; Bankiewicz, Krystof; Kieburtz, Karl; Saarma, Mart; Booms, Sigrid; Huttunen, Henri J.; Kells, Adrian P.; Fiandaca, Massimo S.; Stoessl, A. Jon; Eidelberg, David; Federoff, Howard; Voutilainen, Merja H.; Dexter, David T.; Eberling, Jamie; Brundin, Patrik; Isaacs, Lyndsey; Mursaleen, Leah; Bresolin, Eros; Carroll, Camille; Coles, Alasdair; Fiske, Brian; Matthews, Helen; Lungu, Codrin; Wyse, Richard K.; Stott, Simon; Lang, Anthony E. (2020)
    The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.
  • Chmielarz, Piotr; Er, Safak; Konovalova, Julia; Bandres, Laura; Hlushchuk, Irena; Albert, Katrina; Panhelainen, Anne; Luk, Kelvin; Airavaara, Mikko; Domanskyi, Andrii (2020)
    Background Parkinson's disease (PD) is associated with proteostasis disturbances and accumulation of misfolded alpha-synuclein (alpha-syn), a cytosolic protein present in high concentrations at pre-synaptic neuronal terminals. It is a primary constituent of intracellular protein aggregates known as Lewy neurites or Lewy bodies. Progression of Lewy pathology caused by the prion-like self-templating properties of misfolded alpha-syn is a characteristic feature in the brains of PD patients. Glial cell line-derived neurotrophic factor (GDNF) promotes survival of mature dopamine (DA) neurons in vitro and in vivo. However, the data on its effect on Lewy pathology is controversial. Objectives We studied the effects of GDNF on misfolded alpha-syn accumulation in DA neurons. Methods Lewy pathology progression was modeled by the application of alpha-syn preformed fibrils in cultured DA neurons and in the adult mice. Results We discovered that GDNF prevented accumulation of misfolded alpha-syn in DA neurons in culture and in vivo. These effects were abolished by deletion of receptor tyrosine kinase rearranged during transfection (RET) or by inhibitors of corresponding signaling pathway. Expression of constitutively active RET protected DA neurons from fibril-induced alpha-syn accumulation. Conclusions For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded alpha-syn propagation in DA neurons, uncovered underlying receptors, and investigated the involved signaling pathways. These results demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathology spread at early stages of PD. (c) 2020 International Parkinson and Movement Disorder Society