Browsing by Subject "neurodegeneration"

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  • Oamen, Henry Patrick; Romero, Nathaly Romero; Knuckles, Philip; Saarikangas, Juha; Radman-Livaja, Marta; Dong, Yuhong; Caudron, Fabrice (2022)
    Most neurodegenerative diseases such as Alzheimer's disease are proteinopathies linked to the toxicity of amyloid oligomers. Treatments to delay or cure these diseases are lacking. Using budding yeast, we report that the natural lipid tripentadecanoin induces expression of the nitric oxide oxidoreductase Yhb1 to prevent the formation of protein aggregates during aging and extends replicative lifespan. In mammals, tripentadecanoin induces expression of the Yhb1 orthologue, neuroglobin, to protect neurons against amyloid toxicity. Tripentadecanoin also rescues photoreceptors in a mouse model of retinal degeneration and retinal ganglion cells in a Rhesus monkey model of optic atrophy. Together, we propose that tripentadecanoin affects p-bodies to induce neuroglobin expression and offers a potential treatment for proteinopathies and retinal neurodegeneration.
  • Peteri, Ulla-Kaisa; Niukkanen, Mikael; Castren, Maija L. (2019)
    To an increasing extent, astrocytes are connected with various neuropathologies. Astrocytes comprise of a heterogeneous population of cells with region- and species-specific properties. The frontal cortex exhibits high levels of plasticity that is required for high cognitive functions and memory making this region especially susceptible to damage. Aberrations in the frontal cortex are involved with several cognitive disorders, including Alzheimer's disease, Huntington's disease and frontotemporal dementia. Human induced pluripotent stem cells (iPSCs) provide an alternative for disease modeling and offer possibilities for studies to investigate pathological mechanisms in a cell type-specific manner. Patient-specific iPSC-derived astrocytes have been shown to recapitulate several disease phenotypes. Addressing astrocyte heterogeneity may provide an improved understanding of the mechanisms underlying neurodegenerative diseases.
  • Eskelinen, Eeva-Liisa (2019)
    Autophagy is a conserved catabolic process that delivers cytoplasmic components and organelles to lysosomes for degradation and recycling. This pathway serves to degrade nonfunctional organelles and aggregate-prone proteins, as well as to produce substrates for energy production and biosynthesis. Autophagy is especially important for the maintenance of stem cells, and for the survival and homeostasis of post-mitotic cells like neurons. Functional autophagy promotes longevity in several model organisms. Autophagy regulates immunity and inflammation at several levels and has both anti- and pro-tumorigenic roles in cancer. This review provides a concise overview of autophagy and its importance in cellular and organismal homeostasis, with emphasis on aging, stem cells, neuronal cells, immunity, inflammation, and cancer.
  • Leikas, Juuso V.; Kohtala, Samuel; Theilmann, Wiebke; Jalkanen, Aaro J.; Forsberg, Markus M.; Rantamaki, Tomi (2017)
    Parkinson's disease (PD) is a progressive neurodegenerative movement disorder primarily affecting the nigrostriatal dopaminergic system. The link between heightened activity of glycogen synthase kinase 3 beta (GSK313) and neurodegenerative processes has encouraged investigation into the potential disease-modifying effects of novel GSK3 beta inhibitors in experimental models of PD. Therefore, the intriguing ability of several anesthetics to readily inhibit GSK3 beta within the cortex and hippocampus led us to investigate the effects of brief isoflurane anesthesia on striatal GSK3 beta signaling in nave rats and in a rat model of early-stage PD. Deep but brief (20-min) isoflurane anesthesia exposure increased the phosphorylation of GSK3 beta at the inhibitory Ser9 residue, and induced phosphorylation of AKT(Thr308) (protein kinase B; negative regulator of GSK3 beta) in the striatum of naive rats and rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesion. The 6-OHDA protocol produced gradual functional deficiency within the nigrostriatal pathway, reflected as a preference for using the limb ipsilateral to the lesioned striatum at 2 weeks post 6-OHDA. Interestingly, such motor impairment was not observed in animals exposed to four consecutive isoflurane treatments (20-min anesthesia every 48 h; treatments started 7 days after 6-OHDA delivery). However, isoflurane had no effect on striatal or nigral tyrosine hydroxylase (a marker of dopaminergic neurons) protein levels. This brief report provides promising results regarding the therapeutic potential and neurobiological mechanisms of anesthetics in experimental models of PD and guides development of novel disease-modifying therapies.
  • Gupta, Govind; Gliga, Anda; Hedberg, Jonas; Serra, Angela; Greco, Dario; Odnevall Wallinder, Inger; Fadeel, Bengt (2020)
    Abstract The neurotoxicity of hard metal-based nanoparticles (NPs) remains poorly understood. Here, we deployed the human neuroblastoma cell line SH-SY5Y differentiated or not into dopaminergic- and cholinergic-like neurons to study the impact of tungsten carbide (WC) NPs, WC NPs sintered with cobalt (Co), or Co NPs versus soluble CoCl2. Co NPs and Co salt triggered a dose-dependent cytotoxicity with an increase in cytosolic calcium, lipid peroxidation, and depletion of glutathione (GSH). Co NPs and Co salt also suppressed glutathione peroxidase 4 (GPX4) mRNA and protein expression. Co-exposed cells were rescued by N-acetylcysteine (NAC), a precursor of GSH, and partially by liproxstatin-1, an inhibitor of lipid peroxidation. Furthermore, in silico analyses predicted a significant correlation, based on similarities in gene expression profiles, between Co-containing NPs and Parkinson's disease, and changes in the expression of selected genes were validated by RT-PCR. Finally, experiments using primary human dopaminergic neurons demonstrated cytotoxicity and GSH depletion in response to Co NPs and CoCl2 with loss of axonal integrity. Overall, these data point to a marked neurotoxic potential of Co-based but not WC NPs and show that neuronal cell death may occur through a ferroptosis-like mechanism.
  • Claesson, Tor-björn; Putaala, Jukka; Shams, Sara; Salli, Eero; Gordin, Daniel; Liebkind, Ron; Forsblom, Carol; Summanen, Paula A.; Tatlisumak, Turgut; Groop, Per-Henrik; Martola, Juha; Thorn, Lena M. (2020)
    Background and purpose: Degenerative change of the corpus callosum might serve as a clinically useful surrogate marker for net pathological cerebral impact of diabetes type 1. We compared manual and automatic measurements of the corpus callosum, as well as differences in callosal cross-sectional area between subjects with type 1 diabetes and healthy controls. Materials and methods: This is a cross-sectional study on 188 neurologically asymptomatic participants with type 1 diabetes and 30 healthy age- and sex-matched control subjects, recruited as part of the Finnish Diabetic Nephropathy Study. All participants underwent clinical work-up and brain MRI. Callosal area was manually measured and callosal volume quantified with FreeSurfer. The measures were normalized using manually measured mid-sagittal intracranial area and volumetric intracranial volume, respectively. Results: Manual and automatic measurements correlated well (callosal area vs. volume: rho = 0.83, p <0.001 and mid-sagittal area vs. intracranial volume: rho = 0.82, p <0.001). We found no significant differences in the callosal measures between cases and controls. In type 1 diabetes, the lowest quartile of normalized callosal area was associated with higher insulin doses (p = 0.029) and reduced insulin sensitivity (p = 0.033). In addition, participants with more than two cerebral microbleeds had smaller callosal area (p = 0.002). Conclusion: Manually measured callosal area and automatically segmented are interchangeable. The association seen between callosal size with cerebral microbleeds and insulin resistance is indicative of small vessel disease pathology in diabetes type 1.
  • Choo, Xin Yi; Liddell, Jeffrey R.; Huuskonen, Mikko T.; Grubman, Alexandra; Moujalled, Diane; Roberts, Jessica; Kysenius, Kai; Patten, Lauren; Quek, Hazel; Oikari, Lotta E.; Duncan, Clare; James, Simon A.; McInnes, Lachlan E.; Hayne, David J.; Donnelly, Paul S.; Pollari, Eveliina; Vähätalo, Suvi; Lejavova, Katarina; Kettunen, Mikko; Malm, Tarja; Koistinaho, Jari; White, Anthony R.; Kanninen, Katja M. (2018)
    Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer's disease (AD). Inflammation and biometals are linked at the molecular level through regulation of metal buffering proteins such as the metallothioneins. Even though the molecular connections between metals and inflammation have been demonstrated, little information exists on the effect of copper modulation on brain inflammation. Methods: We demonstrate the immunomodulatory potential of the copper bis(thiosemicarbazone) complex Cu-II(atsm) in an neuroinflammatory model in vivo and describe its anti-inflammatory effects on microglia and astrocytes in vitro. Results: By using a sophisticated in vivo magnetic resonance imaging (MRI) approach, we report the efficacy of Cu-II(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide (LPS). Cu-II(atsm) also induced anti-inflammatory outcomes in primary microglia [significant reductions in nitric oxide (NO), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF)] and astrocytes [significantly reduced NO, MCP-1, and interleukin 6 (IL-6)] in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes. Conclusion: The beneficial effects of Cu-II(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.
  • Kiiskinen, Elina (Helsingin yliopisto, 2022)
    Inclusion bodies are intracellular limited aggregates that consist of subcellular components, such as proteins, that have folded incorrectly, accumulated, and not been eliminated by cells protective systems. Neuronal cytoplasmic inclusion bodies are formed in many human neurodegenerative diseases but have also been found in some canine neurodegenerative diseases. Malfunction of protein degradation systems has been linked to formation of inclusion bodies but the underlying purpose behind inclusion body formation is still often unknown. Lagotto Romagnolo (LR) is an old Italian dog breed. Several neurological diseases, such as benign familial juvenile epilepsy and cerebellar cortical abiotrophy, are known to occur among LR dogs. Eosinophilic neuronal cytoplasmic inclusion bodies have been discovered in brain samples of LR dogs with benign familial juvenile epilepsy and in LRs without clinical signs of disease. This licentiate thesis consists of a literature review and a histological study. The literature review introduces neuronal inclusion bodies and their known contents in general, as well as human and canine diseases linked to these inclusion bodies along with cellular processes that might be linked to the formation of inclusions. The most common staining methods used for neuronal inclusion bodies are also presented briefly. The study is a descriptive, retrospective study aiming to define the content of neuronal cytoplasmic inclusion bodies of LR dogs. The study material consisted of formalin-fixed, paraffin-embedded brain samples from four LR dogs that underwent autopsy at Section for Veterinary Pathology, University of Helsinki, from 2012 to 2018. One female dog with and three female dogs without neurological signs, all with a finding of intraneuronal cytoplasmic inclusions in the brain sections stained with hematoxylin-eosin-stain, were chosen for further stainings. The geniculate nuclei brain samples were stained histochemically for glycoproteins, lipoproteins, basic amino acids, and fibrin. Immunohistochemical stains used were ubiquitin, a-synuclein, β-amyloid, p62, LC3 and 1C2. The inclusions stained positively with Mallory phosphotungstic acid hematoxylin staining (PTAH) in all tested samples. PTAH is a histochemical stain with a high affinity to basic amino acids lysine, arginine, and histidine. Neuronal inclusion bodies that are positive on PTAH have been found as spontaneous age-related lesions in laboratory mice. In electron microscopy, the inclusion material was electron dense and finely granular with some small vesicular profiles without a limiting membrane. In conclusion, the neuronal inclusion bodies in geniculate nuclei of LR dogs in this study contain basic amino acids and not carbohydrates, lipids, or fibrinous material. The inclusion bodies are, however, not targeted for degradation as no p62, LC3 or ubiquitin signal was detected. Aggregation of a-synuclein or β-amyloid were also not detected within the inclusion.
  • Anttila, Emmi (Helsingin yliopisto, 2021)
    Mild traumatic brain injury (TBI) is defined as an injury that disrupts the normal functioning of the brain and is the result of external force to the head. It is the most common type of traumatic head injury, and it is common especially in contact sports and within military personnel. Mild TBI typically causes no clear structural changes to the head, but it can induce persistent clinical symptoms, as well as microscopic pathological changes to the brain that may eventually lead to neurodegeneration and increase the risk for several diseases. Mild TBI is a risk factor for several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy. The primary objective of this study was to develop a repetitive mild TBI mouse model for future research purposes in the field of head trauma and neurodegeneration. The injury was induced as a closed head injury with an electromagnetic impactor. Literature and pilot experiments were used to define the parameters of the impactor required to induce a brain injury of desired severity. The characterization criteria of the mild TBI model considered the criteria used to define human mild TBI, as well as long term effects often reported after repetitive mild TBI: neurodegeneration as tau protein related pathology, neuroinflammation, and memory deficits. The secondary objective of this study was to tentatively test a prolyl oligopeptidase (PREP) inhibitor on the behavioral and histological effects of mild TBI. The functioning of the mild TBI model was studied by histopathological and behavioral assessments. After baseline behavioral assessment and repetitive (1 injury every 24 hours altogether 5 times) mild TBI inductions, the mice were monitored for approximately 3 months, during which several rounds of behavioral tests were performed. Barnes maze and novel object recognition tests were used to assess memory functions, and locomotor activity test was used to assess general locomotor activity. After euthanasia, brain histopathology was performed to study the amount of tau protein and the level of neuroinflammation. Due to the low number of animals in the study, the results are directional and need to be confirmed in subsequent studies. The histopathology showed greater amount of neuroinflammation and tau protein in the brains of injured mice, but statistical evaluations could not be made. Memory functions were slightly worse in the injured mice compared to controls, but significance of the results is unclear. Locomotor activity was not influenced by the mild TBIs. PREP inhibition treatment increased the locomotor activity of the mice, but the significance is unclear. The mild TBI model seems promising and the characterization criteria were partially met. The results of the study need to be verified in subsequent studies with a greater amount of animals. The model developed here can be used to study the involvement of head trauma in neurodegeneration, as well as treatment alternatives to changes caused by mild TBIs. As there currently are no curative treatments to neurodegenerative diseases, research regarding neurodegeneration and its risk factors is highly important.
  • Walkowicz, Lucyna; Kijak, Ewelina; Krzeptowski, Wojciech; Gorska-Andrzejak, Jolanta; Stratoulias, Vassilis; Woznicka, Olga; Chwastek, Elzbieta; Heino, Tapio I.; Pyza, Elzbieta M. (2017)
    In Drosophila melanogaster, mesencephalic astrocyte-derived neurotrophic factor(DmMANF) is an evolutionarily conserved ortholog of mammalian MANF and cerebral dopamine neurotrophic factor (CDNF), which have been shown to promote the survival of dopaminergic neurons in the brain. We observed especially high levels of DmMANF in the visual system of Drosophil a, particularly in the first optic neuropil (lamina). In the lamina, DmMANF was found in glial cells (surface and epithelial glia), photoreceptors and interneurons. Interestingly, silencing of DmMANF in all neurons or specifically in photoreceptors or L2 interneurons had no impact on the structure of the visual system. However, downregulation of DmMANF in glial cells induced degeneration of the lamina. Remarkably, this degeneration in the form of holes and/or tightly packed membranes was observed only in the lamina epithelial glial cells. Those membranes seem to originate from the endoplasmic reticulum, which forms autophagosome membranes. Moreover, capitate projections, the epithelial glia invaginations into photoreceptor terminals that are involved in recycling of the photoreceptor neurotransmitter histamine, were less numerous after DmMANF silencing either in neurons or glial cells. The distribution of the alpha subunit of Na+/K+-ATPase protein in the lamina cell membranes was also changed. At the behavioral level, silencing of DmMANF either in neurons or glial cells affected the daily activity/sleep pattern, and flies showed less activity during the day but higher activity during the night than did controls. In the case of silencing in glia, the lifespan of flies was also shortened. The obtained results showed that DmMANF regulates many functions in the brain, particularly those dependent on glial cells.
  • Kujawska, Malgorzata; Domanskyi, Andrii; Kreiner, Grzegorz (2021)
  • Collier, Jack J.; Suomi, Fumi; Olahova, Monika; McWilliams, Thomas G.; Taylor, Robert W. (2021)
    The cardinal stages of macroautophagy are driven by core autophagy-related (ATG) proteins, whose ablation largely abolishes intracellular turnover. Disrupting ATG genes is paradigmatic of studying autophagy deficiency, yet emerging data suggest that ATG proteins have extensive biological importance beyond autophagic elimination. An important example is ATG7, an essential autophagy effector enzyme that in concert with other ATG proteins, also regulates immunity, cell death and protein secretion, and independently regulates the cell cycle and apoptosis. Recently, a direct association between ATG7 dysfunction and disease was established in patients with biallelic ATG7 variants and childhood-onset neuropathology. Moreover, a prodigious body of evidence supports a role for ATG7 in protecting against complex disease states in model organisms, although how dysfunctional ATG7 contributes to manifestation of these diseases, including cancer, neurodegeneration and infection, in humans remains unclear. Here, we systematically review the biological functions of ATG7, discussing the impact of its impairment on signalling pathways and human pathology. Future studies illuminating the molecular relationship between ATG7 dysfunction and disease will expedite therapies for disorders involving ATG7 deficiency and/or impaired autophagy.
  • 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.
  • Nykänen, Heidi (Helsingin yliopisto, 2022)
    Parkinsonin tauti on maailman yleisin hermorappeumaa aiheuttava liikehäiriösairaus. Taudin ilmaantuvuus- ja esiintyvyysluvut ovat jatkuvassa nousussa, mitä väestön ikääntyminen ei yksin selitä. Taudin patologisia löydöksiä ovat alfasynukleiinin kertyminen ja vääränlaisesta laskostumisesta johtuva aggregaatio, Lewy neuriittien ja kappaleiden kertyminen sekä dopaminergisten hermosolujen solukato mustatumakkeesta. Taudin pidemmälle edenneille vaiheille on tyypillistä vaikea toimintakyvyttömyys ja elinajanodotteen lasku. Nykyiset hoitomuodot niin Parkinsonin taudille, kuin muillekin hermorappeumasairauksille ovat ainoastaan oireita lievittäviä. Onnistuneeseen lääkekehitykseen vaaditaan parannusta eläinmallien validiteetin jokaisella alatasolla. Parkinsonin taudin käytössä olevissa prekliinisissä eläinmalleissa on huono ilmivaliditeetti monien potilailla tehtyjen patologisten löydösten puuttuessa. Tässä tutkielmassa esitän uudenlaisen SynFib rottamallin Parkinsonin tautiin. Eksogeenisesti valmistettuja ihmisen alfasynukleiinifibrillejä injisoitiin yhdessä alfasynukleiinia ekspressoivien virusvektoreiden kanssa mustatumakkeeseen. Injektio aiheutti intensiivisen ja etenevän alfasynukleiinista johtuvan patologian ja merkittävän dopaminergisen soluvaurion. Taudin etenemistä seurattiin pitkittäistutkimuksessa positroniemissiotomografialla ja toiminnallisia puutteita arvioitiin synapsitiheydessä, inflammaatiossa ja dopaminergisessa järjestelmässä 16 viikon ajan. Havaitsin aivokudoksen tulehduksen ja dopaminergisen ipsilateraalisen soluvaurion lisääntyneen merkittävästi. Kahden viikon kohdalla synapsitiheys oli merkittävästi vähentynyt ipsilateraalisesti ja taudin leviäminen kontralateraaliselle puolelle oli alkanut.
  • Mannistö, Pekka T.; Garcia-Horsman, J. Arturo (2017)
    In the aging brain, the correct balance of neural transmission and its regulation is of particular significance, and neuropeptides have a significant role. Prolyl oligopeptidase (PREP) is a protein highly expressed in brain, and evidence indicates that it is related to aging and in neurodegenration. Although PREP is regarded as a peptidase, the physiological substrates in the brain have not been defined, and after intense research, the molecular mechanisms where this protein is involved have not been defined. We propose that PREP functions as a regulator of other proteins though peptide gated direct interaction. We speculate that, at least in some processes where PREP has shown to be relevant, the peptidase activity is only a consequence of the interactions, and not the main physiological activity.
  • Sree, Sreesha; Parkkinen, Ilmari; Their, Anna; Airavaara, Mikko; Jokitalo, Eija (2021)
    The endoplasmic reticulum (ER) is a multipurpose organelle comprising dynamic structural subdomains, such as ER sheets and tubules, serving to maintain protein, calcium, and lipid homeostasis. In neurons, the single ER is compartmentalized with a careful segregation of the structural subdomains in somatic and neurite (axodendritic) regions. The distribution and arrangement of these ER subdomains varies between different neuronal types. Mutations in ER membrane shaping proteins and morphological changes in the ER are associated with various neurodegenerative diseases implying significance of ER morphology in maintaining neuronal integrity. Specific neurons, such as the highly arborized dopaminergic neurons, are prone to stress and neurodegeneration. Differences in morphology and functionality of ER between the neurons may account for their varied sensitivity to stress and neurodegenerative changes. In this review, we explore the neuronal ER and discuss its distinct morphological attributes and specific functions. We hypothesize that morphological heterogeneity of the ER in neurons is an important factor that accounts for their selective susceptibility to neurodegeneration.
  • Penttinen, Anna-Maija; Parkkinen, Ilmari; Voutilainen, Merja H.; Koskela, Maryna; Bäck, Susanne; Their, Anna; Richie, Christopher T.; Domanskyi, Andrii; Harvey, Brandon K.; Tuominen, Raimo K.; Nevalaita, Liina; Saarma, Mart; Airavaara, Mikko (2018)
    Glial cell line-derived neurotrophic factor (GDNF) is one of the most studied neurotrophic factors. GDNF has two splice isoforms, full-length pre-alpha-pro-GDNF (u-GDNF) and pre-beta-pro-GDNF (beta-GDNF), which has a 26 amino acid deletion in the pro-region. Thus far, studies have focused solely on the u-GDNF isoform, and nothing is known about the in vivo effects of the shorter beta-GDNF variant. Here we compare for the first time the effects of overexpressed cx-GDNF and beta-GDNF in non-lesioned rat striatum and the partial 6-hydroxydopamine lesion model of Parkinson's disease. GDNF isoforms were overexpressed with their native pre-pro-sequences in the striatum using an adeno-associated virus (AAV) vector, and the effects on motor performance and dopaminergic phenotype of the nigrostriatal pathway were assessed. In the non-lesioned striatum, both isoforms increased the density of dopamine transporter-positive fibers at 3 weeks after viral vector delivery. Although both isoforms increased the activity of the animals in cylinder assay, only u-GDNF enhanced the use of contralateral paw. Four weeks later, the striatal tyrosine hydroxylase (TH)-immunoreactivity was decreased in both u-GDNF and 1-GDNF treated animals. In the neuroprotection assay, both GDNF splice isoforms increased the number of TH-immunoreactive cells in the substantia nigra but did not promote behavioral recovery based on amphetamine-induced rotation or cylinder assays. Thus, the shorter GDNF isoform, beta-GDNF, and the full-length alpha-isoform have comparable neuroprotective efficacy on dopamine neurons of the nigrostriatal circuitry.
  • Mahato, Arun Kumar; Sidorova, Yulia A. (2020)
    Rearranged during transfection (RET) is the tyrosine kinase receptor that under normal circumstances interacts with ligand at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism. RET plays a pivotal role in the development of both peripheral and central nervous systems. RET is expressed from early stages of embryogenesis and remains expressed throughout all life stages. Mutations either activating or inhibiting RET result in several aggressive diseases, namely cancer and Hirschsprung disease. However, the physiological ligand-dependent activation of RET receptor is important for the survival and maintenance of several neuronal populations, appetite, and weight gain control, thus providing an opportunity for the development of disease-modifying therapeutics against neurodegeneration and obesity. In this review, we describe the structure of RET, its signaling, and its role in both normal conditions as well as in several disorders. We highlight the differences in the signaling and outcomes of constitutive and ligand-induced RET activation. Finally, we review the data on recently developed small molecular weight RET agonists and their potential for the treatment of various diseases.
  • Ylä-Anttila, Päivi; Eskelinen, Eeva-Liisa (2018)
    Autophagy is an evolutionarily conserved degradation pathway for cells to maintain homeostasis, produce energy, degrade misfolded proteins and damaged organelles, and fight against intracellular pathogens. The process of autophagy entails the isolation of cytoplasmic cargo into double membrane bound autophagosomes that undergo maturation by fusion with endosomes and lysosomes in order to obtain degradation capacity. RAB proteins regulate intracellular vesicle trafficking events including autophagy. RAB24 is an atypical RAB protein that is required for the clearance of late autophagic vacuoles under basal conditions. RAB24 has also been connected to several diseases including ataxia, cancer and tuberculosis. This review gives a short summary on autophagy and RAB proteins, and an overview on the current knowledge on the roles of RAB24 in autophagy and disease.