ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome Mailis Liiv, Annika Vaarmann, Dzhamilja Safiulina, Vinay Choubey, Ruby Gupta, et al. Nature Communications, 2024 Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.
Levodopa Impairs Lysosomal Function in Sensory Neurons In Vitro Oyedele J. Olaoye, Asya Esin Aksoy, Santeri V. Hyytiäinen, Aia A. Narits, Miriam A. Hickey Biology, 2024 Parkinson’s disease (PD) is the second-most common neurodegenerative disease worldwide. Patients are diagnosed based upon movement disorders, including bradykinesia, tremor and stiffness of movement. However, non-motor signs, including constipation, rapid eye movement sleep behavior disorder, smell deficits and pain are well recognized. Peripheral neuropathy is also increasingly recognized, as the vast majority of patients show reduced intraepidermal nerve fibers, and sensory nerve conduction and sensory function is also impaired. Many case studies in the literature show that high-dose levodopa may induce or exacerbate neuropathy in PD, which is thought to involve levodopa’s metabolism to homocysteine. Here, we treated primary cultures of dorsal root ganglia and a sensory neuronal cell line with levodopa to examine effects on cell morphology, mitochondrial content and physiology, and lysosomal function. High-dose levodopa reduced mitochondrial membrane potential. At concentrations observed in the patient, levodopa enhanced immunoreactivity to beta III tubulin. Critically, levodopa reduced lysosomal content and also reduced the proportion of lysosomes that were acidic, thereby impairing their function, whereas homocysteine tended to increase lysosome content. Levodopa is a critically important drug for the treatment of PD. However, our data suggest that at concentrations observed in the patient, it has deleterious effects on sensory neurons that are not related to homocysteine.
No Evidence of Sensory Neuropathy in a Traditional Mouse Model of Idiopathic Parkinson’s Disease Mahvish Faisal, Anna Rusetskaya, Liis Väli, Pille Taba, Ave Minajeva, et al. Cells, 2024 Parkinson’s disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems are affected can contribute to the development of targeted therapies and deepen our understanding of the pathophysiology of PD. Although the cause of sporadic PD is unknown, chronic exposure to the pesticide rotenone in humans increases the risk of developing the disease. Here, we aimed to investigate whether peripheral neuropathy is present in a traditional model of PD. Mice receiving intrastriatal rotenone showed greatly reduced dopamine terminals in the striatum and a reduction in tyrosine hydroxylase-positive neurons in the Substantia nigra pars compacta and developed progressive motor impairments in hindlimb stepping and rotarod but no change in spontaneous activity. Interestingly, repeated testing using gold-standard protocols showed no change in gut motility, a well-known non-motor symptom of PD. Importantly, we did not observe any change in heat, cold, or touch sensitivity, again based upon repeated testing with well-validated protocols that were statistically well powered. Therefore, this traditional model fails to replicate PD, and our data again reiterate the importance of the periphery to the disorder.
Preclinical trials in Alzheimer's disease: Sample size and effect size for behavioural and neuropathological outcomes in 5xFAD mice Mahvish Faisal, Jana Aid, Bekzod Nodirov, Benjamin Lee, Miriam A. Hickey Plos One, 2023 5xFAD transgenic (TG) mice are used widely in AD preclinical trials; however, data on sample sizes are largely unaddressed. We therefore performed estimates of sample sizes and effect sizes for typical behavioural and neuropathological outcome measures in TG 5xFAD mice, based upon data from single-sex (female) groups. Group-size estimates to detect normalisation of TG body weight to WT littermate levels at 5.5m of age were N = 9–15 depending upon algorithm. However, by 1 year of age, group sizes were small (N = 1 –<6), likely reflecting the large difference between genotypes at this age. To detect normalisation of TG open-field hyperactivity to WT levels at 13-14m, group sizes were also small (N = 6–8). Cued learning in the Morris water maze (MWM) was normal in Young TG mice (5m of age). Mild deficits were noted during MWM spatial learning and memory. MWM reversal learning and memory revealed greater impairment, and groups of up to 22 TG mice were estimated to detect normalisation to WT performance. In contrast, Aged TG mice (tested between 13 and 14m) failed to complete the visual learning (non-spatial) phase of MWM learning, likely due to a failure to recognise the platform as an escape. Estimates of group size to detect normalisation of this severe impairment were small (N = 6–9, depending upon algorithm). Other cognitive tests including spontaneous and forced alternation and novel-object recognition either failed to reveal deficits in TG mice or deficits were negligible. For neuropathological outcomes, plaque load, astrocytosis and microgliosis in frontal cortex and hippocampus were quantified in TG mice aged 2m, 4m and 6m. Sample-size estimates were ≤9 to detect the equivalent of a reduction in plaque load to the level of 2m-old TG mice or the equivalent of normalisation of neuroinflammation outcomes. However, for a smaller effect size of 30%, larger groups of up to 21 mice were estimated. In light of published guidelines on preclinical trial design, these data may be used to provide provisional sample sizes and optimise preclinical trials in 5xFAD TG mice.
Enhanced Anxiety and Olfactory Microglial Activation in Early-Stage Familial Alzheimer’s Disease Mouse Model Keerthana Chithanathan, Fang-Ling Xuan, Miriam Ann Hickey, Li Tian Biology, 2022 Anxiety is a known comorbidity and risk factor for conversion to neuroinflammation-mediated dementia in patients with Alzheimer’s disease (AD). Here, we investigated if anxiety occurred as an early endophenotype of mutant familial AD (5 × FAD) male mice and the underlying neuroinflammatory mechanisms. We observed that compared to wildtype (WT) littermates, 5 × FAD mice showed enhanced anxiety at as early as 2 months old (mo). Interestingly, these 5 × FAD male mice had concomitantly increased mRNA levels of pro-inflammatory cytokines such as interleukin 1 beta (Il1b) and tumor necrosis factor (Tnf) in the olfactory bulb (OB) but not the frontal cortex (FC). Increased expression of Tnf in the OB was significantly correlated with the anxious behavior in the FAD but not WT mice. Furthermore, we found more prominent microglial activation and morphological changes in the OB of 2 mo 5 × FAD mice, while only microglial ramification was seen in the FC. To understand if neuroinflammatory changes in the FC could occur at a later stage, we studied 5~6 mo male mice and found that Il1b, interleukin 18 (Il18), and Tnf were upregulated in the FC at this older age. Furthermore, we observed that numbers of microglia and macrophage as well as microglial synaptic pruning, as indicated by phagocytosis of presynaptic component of vesicular glutamate transporter-2, were increased in the OB but not the FC of 5~6 mo 5 × FAD mice. Our findings demonstrated the OB as a more sensitive brain region than the cerebral cortex for microglia-mediated neuroinflammation in association with anxiety in FAD mice and supported the notion that the OB can be an early-stage biomarker in AD.
Early intervention and lifelong treatment with glp1 receptor agonist liraglutide in a wolfram syndrome rat model with an emphasis on visual neurodegeneration, sensorineural hearing loss and diabetic phenotype Toomas Jagomäe, Kadri Seppa, Riin Reimets, Marko Pastak, Mihkel Plaas, et al. Cells, 2021 Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.
Using Rotenone to Model Parkinson's Disease in Mice: A Review of the Role of Pharmacokinetics Jürgen Innos, Miriam A. Hickey Chemical Research in Toxicology, 2021 Rotenone is a naturally occurring toxin that inhibits complex I of the mitochondrial electron transport chain. Several epidemiological studies have shown an increased risk of Parkinson's disease (PD) in individuals exposed chronically to rotenone, and it has received great attention for its ability to reproduce many critical features of PD in animal models. Laboratory studies of rotenone have repeatedly shown that it induces in vivo substantia nigra dopaminergic cell loss, a hallmark of PD neuropathology. Additionally, rotenone induces in vivo aggregation of α-synuclein, the major component of Lewy bodies and Lewy neurites found in the brain of PD patients and another hallmark of PD neuropathology. Some in vivo rotenone models also reproduce peripheral signs of PD, such as reduced intestinal motility and peripheral α-synuclein aggregation, both of which are thought to precede classical signs of PD in humans, such as cogwheel rigidity, bradykinesia, and resting tremor. Nevertheless, variability has been noted in cohorts of animals exposed to the same rotenone exposure regimen and also between cohorts exposed to similar doses of rotenone. Low doses, administered chronically, may reproduce PD symptoms and neuropathology more faithfully than excessively high doses, but overlap between toxicity and parkinsonian motor phenotypes makes it difficult to separate if behavior is examined in isolation. Rotenone degrades when exposed to light or water, and choice of vehicle may affect outcome. Rotenone is metabolized extensively in vivo, and choice of route of exposure influences greatly the dose used. However, male rodents may be capable of greater metabolism of rotenone, which could therefore reduce their total body exposure when compared with female rodents. The pharmacokinetics of rotenone has been studied extensively, over many decades. Here, we review these pharmacokinetics and models of PD using this important piscicide.
Curcumin Formulations and Trials: What’s New in Neurological Diseases Stella Gagliardi, Carlo Morasso, Polychronis Stivaktakis, Cecilia Pandini, Veronica Tinelli, et al. Molecules, 2020 Curcumin’s pharmacological properties and its possible benefits for neurological diseases and dementia have been much debated. In vitro experiments show that curcumin modulates several key physiological pathways of importance for neurology. However, in vivo studies have not always matched expectations. Thus, improved formulations of curcumin are emerging as powerful tools in overcoming the bioavailability and stability limitations of curcumin. New studies in animal models and recent double-blinded, placebo-controlled clinical trials using some of these new formulations are finally beginning to show that curcumin could be used for the treatment of cognitive decline. Ultimately, this work could ease the burden caused by a group of diseases that are becoming a global emergency because of the unprecedented growth in the number of people aged 65 and over worldwide. In this review, we discuss curcumin’s main mechanisms of action and also data from in vivo experiments on the effects of curcumin on cognitive decline.
Kuidas viia teaduspõhised teadmised inimesteni? R Mändar, MA Hickey Eesti Arst , 2026 2026
Early trigeminal and sensory impairment and lysosomal dysfunction in accurate models of Wolfram syndrome K Tulva, A Pirajev, A Zeb, AE Aksoy, A Bello, B Lee, BF Guðjónsson, ... Experimental Neurology 385, 115099 , 2025 2025 Citations: 2
Enhancing Medical Science Engagement through International Research Exchange: Objectives, Activities, and Outcomes M Jürgenson, A García-Llorca, A Sarv, T Eysteinsson, M Hickey bioRxiv, 2025.02. 26.640317 , 2025 2025
Exploring the anti-inflammatory effects of curcumin encapsulated within ferritin nanocages: a comprehensive in vivo and in vitro study in Alzheimer’s disease C Morasso, M Truffi, V Tinelli, P Stivaktakis, R Di Gerlando, D Francesca, ... Journal of Nanobiotechnology 22 (1), 718 , 2024 2024 Citations: 21
Levodopa impairs lysosomal function in sensory neurons in vitro OJ Olaoye, AE Aksoy, SV Hyytiäinen, AA Narits, MA Hickey Biology 13 (11), 893 , 2024 2024 Citations: 1
ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome M Liiv, A Vaarmann, D Safiulina, V Choubey, R Gupta, M Kuum, ... Nature Communications 15 (1), 6143 , 2024 2024 Citations: 59
No evidence of sensory neuropathy in a traditional mouse model of idiopathic Parkinson’s disease M Faisal, A Rusetskaya, L Väli, P Taba, A Minajeva, MA Hickey Cells 13 (10), 799 , 2024 2024 Citations: 4
Research data for Early trigeminal and sensory impairment and lysosomal dysfunction in accurate models of Wolfram syndrome M Hickey University of Tartu , 2024 2024
Levodopa impairs lysosomal function in sensory neurons in vitro M Hickey University of Tartu , 2024 2024
Preclinical trials in Alzheimer’s disease: Sample size and effect size for behavioural and neuropathological outcomes in 5xFAD mice M Faisal, J Aid, B Nodirov, B Lee, MA Hickey PLoS One 18 (4), e0281003 , 2023 2023 Citations: 16
Enhanced anxiety and olfactory microglial activation in early-stage familial alzheimer’s disease mouse model K Chithanathan, FL Xuan, MA Hickey, L Tian Biology 11 (6), 938 , 2022 2022 Citations: 10
Enhanced Anxiety and Olfactory Microglial Activation in Early-Stage Familial Alzheimer’s Disease Mouse Model. Biology 2022, 11, 938 K Chithanathan, FL Xuan, MA Hickey, L Tian s Note: MDPI stays neutral with regard to jurisdictional claims in published … , 2022 2022
Early intervention and lifelong treatment with GLP1 receptor agonist liraglutide in a wolfram syndrome rat model with an emphasis on visual neurodegeneration, sensorineural … T Jagomäe, K Seppa, R Reimets, M Pastak, M Plaas, MA Hickey, ... Cells 10 (11), 3193 , 2021 2021 Citations: 29
Using rotenone to model Parkinson’s disease in mice: a review of the role of pharmacokinetics J Innos, MA Hickey Chemical research in toxicology 34 (5), 1223-1239 , 2021 2021 Citations: 137
Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural … T Jagomae, K Seppa, R Reimets, M Pastak, M Plaas, MA Hickey, ... doi. org/10.3390/cells10113193 , 2021 2021 Citations: 1
Curcumin formulations and trials: what’s new in neurological diseases S Gagliardi, C Morasso, P Stivaktakis, C Pandini, V Tinelli, A Tsatsakis, ... Molecules 25 (22), 5389 , 2020 2020 Citations: 49
Phenotype onset in Huntington’s disease knock‐in mice is correlated with the incomplete splicing of the mutant huntingtin gene NR Franich, MA Hickey, C Zhu, GF Osborne, N Ali, T Chu, NH Bove, ... Journal of neuroscience research 97 (12), 1590-1605 , 2019 2019 Citations: 56
Mitochondrial transport proteins RHOT1 and RHOT2 serve as docking sites for PRKN-mediated mitophagy D Safiulina, M Kuum, V Choubey, MA Hickey, A Kaasik Autophagy 15 (5), 930-931 , 2019 2019 Citations: 32
Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders K Singh, M Jayaram, M Kaare, E Leidmaa, T Jagomäe, I Heinla, ... Scientific Reports 9 (1), 5457 , 2019 2019 Citations: 83
Miro proteins prime mitochondria for Parkin translocation and mitophagy D Safiulina, M Kuum, V Choubey, N Gogichaishvili, J Liiv, MA Hickey, ... The EMBO journal 38 (2), EMBJ201899384 , 2019 2019 Citations: 142
MOST CITED SCHOLAR PUBLICATIONS
Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice MA Hickey, A Kosmalska, J Enayati, R Cohen, S Zeitlin, MS Levine, ... Neuroscience 157 (1), 280-295 , 2008 2008 Citations: 266
Apoptosis in Huntington's disease MA Hickey, MF Chesselet Progress in Neuro-Psychopharmacology and Biological Psychiatry 27 (2), 255-265 , 2003 2003 Citations: 260
Genetic mouse models of Huntington's and Parkinson's diseases: Illuminating but imperfect MS Levine, C Cepeda, MA Hickey, SM Fleming, MF Chesselet Trends in neurosciences 27 (11), 691-697 , 2004 2004 Citations: 252
Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease MA Hickey, C Zhu, V Medvedeva, RP Lerner, S Patassini, NR Franich, ... Molecular Neurodegeneration 7, 12 , 2012 2012 Citations: 175
Role of mitochondrial dynamics in neuronal development: mechanism for Wolfram syndrome M Cagalinec, M Liiv, Z Hodurova, MA Hickey, A Vaarmann, M Mandel, ... PLoS biology 14 (7), e1002511 , 2016 2016 Citations: 168
Mutant huntingtin-impaired degradation of β-catenin causes neurotoxicity in Huntington's disease JD Godin, G Poizat, MA Hickey, F Maschat, S Humbert The EMBO journal 29 (14), 2433 , 2010 2010 Citations: 150
Early behavioral deficits in R6/2 mice suitable for use in preclinical drug testing MA Hickey, K Gallant, GG Gross, MS Levine, MF Chesselet Neurobiology of disease 20 (1), 1-11 , 2005 2005 Citations: 150
Miro proteins prime mitochondria for Parkin translocation and mitophagy D Safiulina, M Kuum, V Choubey, N Gogichaishvili, J Liiv, MA Hickey, ... The EMBO journal 38 (2), EMBJ201899384 , 2019 2019 Citations: 142
Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models J Phan, MA Hickey, P Zhang, MF Chesselet, K Reue Human molecular genetics 18 (6), 1006-1016 , 2009 2009 Citations: 141
Using rotenone to model Parkinson’s disease in mice: a review of the role of pharmacokinetics J Innos, MA Hickey Chemical research in toxicology 34 (5), 1223-1239 , 2021 2021 Citations: 137
The role of dopamine in motor symptoms in the R6/2 transgenic mouse model of Huntington's disease MA Hickey, GP Reynolds, AJ Morton Journal of neurochemistry 81 (1), 46-59 , 2002 2002 Citations: 137
BECN1 is involved in the initiation of mitophagy: it facilitates PARK2 translocation to mitochondria V Choubey, M Cagalinec, J Liiv, D Safiulina, MA Hickey, M Kuum, M Liiv, ... Autophagy 10 (6), 1105-1119 , 2014 2014 Citations: 129
A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease DM Cummings, Y Alaghband, MA Hickey, PR Joshi, SC Hong, C Zhu, ... Journal of neurophysiology 107 (2), 677-691 , 2012 2012 Citations: 89
The use of transgenic and knock-in mice to study Huntington’s disease MA Hickey, MF Chesselet Cytogenetic and genome research 100 (1-4), 276-286 , 2003 2003 Citations: 88
Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders K Singh, M Jayaram, M Kaare, E Leidmaa, T Jagomäe, I Heinla, ... Scientific Reports 9 (1), 5457 , 2019 2019 Citations: 83
Wfs1-deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration M Plaas, K Seppa, R Reimets, T Jagomäe, M Toots, T Koppel, T Vallisoo, ... Scientific reports 7 (1), 10220 , 2017 2017 Citations: 69
Mice transgenic for the Huntington's disease mutation are resistant to chronic 3‐nitropropionic acid‐induced striatal toxicity MA Hickey, AJ Morton Journal of neurochemistry 75 (5), 2163-2171 , 2000 2000 Citations: 67
ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome M Liiv, A Vaarmann, D Safiulina, V Choubey, R Gupta, M Kuum, ... Nature Communications 15 (1), 6143 , 2024 2024 Citations: 59
Striatal atrophy and dendritic alterations in a knock-in mouse model of Huntington's disease. HMA Lerner RP, Trejo Martinez LD, Zhu C, Chesselet MF Brain Research Bulletin, in press , 2012 2012 Citations: 59
Phenotype onset in Huntington’s disease knock‐in mice is correlated with the incomplete splicing of the mutant huntingtin gene NR Franich, MA Hickey, C Zhu, GF Osborne, N Ali, T Chu, NH Bove, ... Journal of neuroscience research 97 (12), 1590-1605 , 2019 2019 Citations: 56
