Miriam A. Hickey

RESEARCH, TEACHING, or OTHER INTERESTS

Neuroscience, Neurology, Physiology, Behavioral Neuroscience

Scopus Publications

Early trigeminal and sensory impairment and lysosomal dysfunction in accurate models of Wolfram syndrome
Kerli Tulva, Aleksander Pirajev, Akbar Zeb, Asya E. Aksoy, Azizah Bello, Benjamin Lee, Baldvin F. Guðjónsson, Sigridur B. Helgadottir, Toomas Jagomäe, Andrea García-Llorca,et al.
Elsevier BV



Exploring the anti-inflammatory effects of curcumin encapsulated within ferritin nanocages: a comprehensive in vivo and in vitro study in Alzheimer’s disease
Carlo Morasso, Marta Truffi, Veronica Tinelli, Polychronis Stivaktakis, Rosalinda Di Gerlando, Dragoni Francesca, Giulia Perini, Mahvish Faisal, Jana Aid, Bekzod Noridov,et al.
Springer Science and Business Media LLC



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, Malle Kuum, Lucia Janickova, Zuzana Hodurova, Michal Cagalinec, Akbar Zeb,et al.
Springer Science and Business Media LLC
AbstractWolfram 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, and Miriam A. Hickey
MDPI AG
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, and Miriam A. Hickey
MDPI AG
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, and Miriam A. Hickey
Public Library of Science (PLoS)
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, and Li Tian
MDPI AG
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, Miriam A. Hickey, Kaia Grete Kukker, Lieve Moons, Lies De Groef, Eero Vasar,et al.
MDPI AG
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 and Miriam A. Hickey
American Chemical Society (ACS)
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, Aristides Tsatsakis, Davide Prosperi, Miriam Hickey, Fabio Corsi, and Cristina Cereda
MDPI AG
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.


Phenotype onset in Huntington’s disease knock-in mice is correlated with the incomplete splicing of the mutant huntingtin gene
Nicholas R. Franich, Miriam A. Hickey, Chunni Zhu, Georgina F. Osborne, Nadira Ali, Tiffany Chu, Nicholas H. Bove, Vincent Lemesre, Renata P. Lerner, Scott O. Zeitlin,et al.
Wiley
AbstractHuntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat within the huntingtin (HTT) gene. The Q140 and HdhQ150 knock‐in HD mouse models were generated such that HdhQ150 mice have an expanded CAG repeat inserted into the mouse Htt gene, whereas in the Q140s, mouse exon 1 Htt was replaced with a mutated version of human exon 1. By standardizing mouse strain background, breeding to homozygosity and employing sensitive behavioral tests, we demonstrate that the onset of behavioral phenotypes occurs earlier in the Q140 than the HdhQ150 knock‐in mouse models and that huntingtin (HTT) aggregation appears earlier in the striata of Q140 mice. We have previously found that the incomplete splicing of mutant HTT from exon 1 to exon 2 results in the production of a small polyadenylated transcript that encodes the highly pathogenic mutant HTT exon 1 protein. In this report, we have identified a functional consequence of the sequence differences between these two models at the RNA level, in that the level of incomplete splicing, and of the mutant exon 1 HTT protein, are greater in the brains of Q140 mice. While differences in the human and mouse exon 1 HTT proteins (e.g., proline rich sequences) could also contribute to the phenotypic differences, our data indicate that the incomplete splicing of HTT and approaches to lower the levels of the exon 1 HTT transcript should be pursued as therapeutic targets.


Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders
Katyayani Singh, Mohan Jayaram, Maria Kaare, Este Leidmaa, Toomas Jagomäe, Indrek Heinla, Miriam A. Hickey, Allen Kaasik, Michael K. Schäfer, Jürgen Innos,et al.
Springer Science and Business Media LLC
AbstractNeuronal growth regulator 1 (NEGR1) belongs to the immunoglobulin (IgLON) superfamily of cell adhesion molecules involved in cortical layering. Recent functional and genomic studies implicate the role of NEGR1 in a wide spectrum of psychiatric disorders, such as major depression, schizophrenia and autism. Here, we investigated the impact of Negr1 deficiency on brain morphology, neuronal properties and social behavior of mice. In situ hybridization shows Negr1 expression in the brain nuclei which are central modulators of cortical-subcortical connectivity such as the island of Calleja and the reticular nucleus of thalamus. Brain morphological analysis revealed neuroanatomical abnormalities in Negr1−/− mice, including enlargement of ventricles and decrease in the volume of the whole brain, corpus callosum, globus pallidus and hippocampus. Furthermore, decreased number of parvalbumin-positive inhibitory interneurons was evident in Negr1−/− hippocampi. Behaviorally, Negr1−/− mice displayed hyperactivity in social interactions and impairments in social hierarchy. Finally, Negr1 deficiency resulted in disrupted neurite sprouting during neuritogenesis. Our results provide evidence that NEGR1 is required for balancing the ratio of excitatory/inhibitory neurons and proper formation of brain structures, which is prerequisite for adaptive behavioral profiles. Therefore, Negr1−/− mice have a high potential to provide new insights into the neural mechanisms of neuropsychiatric disorders.


Mitochondrial transport proteins RHOT1 and RHOT2 serve as docking sites for PRKN-mediated mitophagy
Dzhamilja Safiulina, Malle Kuum, Vinay Choubey, Miriam A. Hickey, and Allen Kaasik
Informa UK Limited
ABSTRACT The Parkinson disease‐associated proteins PINK1 and PRKN coordinate the ubiquitination of mitochondrial outer membrane proteins to tag them either for degradation or for autophagic clearance of the mitochondrion. The proteins include the mitochondrial trafficking proteins RHOT1 and RHOT2, the removal of which may be required for immobilization of mitochondria prior to mitophagy. Here, we demonstrate that RHOT1 and RHOT2 are not only substrates for PINK1-PRKN‐dependent degradation but that they also play an active role in the process of mitophagy. RHOT1, and likely also RHOT2, may act as a docking site for inactive PRKN prior to mitochondrial damage, thus keeping PRKN in close proximity to its potential substrates and thereby facilitating mitophagy. We also show that RHOT1 functions as a calcium-sensing docking site for PRKN, and we suggest that calcium binding to RHOT is a key step in the calcium‐dependent activation of mitophagy machinery.


Miro proteins prime mitochondria for Parkin translocation and mitophagy
Dzhamilja Safiulina, Malle Kuum, Vinay Choubey, Nana Gogichaishvili, Joanna Liiv, Miriam A Hickey, Michal Cagalinec, Merle Mandel, Akbar Zeb, Mailis Liiv,et al.
Springer Science and Business Media LLC
The Parkinson's disease‐associated protein kinase PINK1 and ubiquitin ligase Parkin coordinate the ubiquitination of mitochondrial proteins, which marks mitochondria for degradation. Miro1, an atypical GTPase involved in mitochondrial trafficking, is one of the substrates tagged by Parkin after mitochondrial damage. Here, we demonstrate that a small pool of Parkin interacts with Miro1 before mitochondrial damage occurs. This interaction does not require PINK1, does not involve ubiquitination of Miro1 and also does not disturb Miro1 function. However, following mitochondrial damage and PINK1 accumulation, this initial pool of Parkin becomes activated, leading to the ubiquitination and degradation of Miro1. Knockdown of Miro proteins reduces Parkin translocation to mitochondria and suppresses mitophagic removal of mitochondria. Moreover, we demonstrate that Miro1 EF‐hand domains control Miro1's ubiquitination and Parkin recruitment to damaged mitochondria, and they protect neurons from glutamate‐induced mitophagy. Together, our results suggest that Miro1 functions as a calcium‐sensitive docking site for Parkin on mitochondria.


Wfs1-deficient rats develop primary symptoms of Wolfram syndrome: Insulin-dependent diabetes, optic nerve atrophy and medullary degeneration
Mario Plaas, Kadri Seppa, Riin Reimets, Toomas Jagomäe, Maarja Toots, Tuuliki Koppel, Tuuli Vallisoo, Mait Nigul, Indrek Heinla, Riho Meier,et al.
Springer Science and Business Media LLC
AbstractWolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5-KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1-ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS.


Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome
Michal Cagalinec, Mailis Liiv, Zuzana Hodurova, Miriam Ann Hickey, Annika Vaarmann, Merle Mandel, Akbar Zeb, Vinay Choubey, Malle Kuum, Dzhamilja Safiulina,et al.
Public Library of Science (PLoS)
Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.


Coenzyme Q10 and Behavior in Huntington's Disease
M.A. Hickey
Elsevier



BECN1 is involved in the initiation of mitophagy: It facilitates PARK2 translocation to mitochondria
Vinay Choubey, Michal Cagalinec, Joanna Liiv, Dzhamilja Safiulina, Miriam A Hickey, Malle Kuum, Mailis Liiv, Tahira Anwar, Eeva-Liisa Eskelinen, and Allen Kaasik
Informa UK Limited
The autophagy protein BECN1/Beclin 1 is known to play a central role in autophagosome formation and maturation. The results presented here demonstrate that BECN1 interacts with the Parkinson disease-related protein PARK2. This interaction does not require PARK2 translocation to mitochondria and occurs mostly in cytosol. However, our results suggest that BECN1 is involved in PARK2 translocation to mitochondria because loss of BECN1 inhibits CCCP- or PINK1 overexpression-induced PARK2 translocation. Our results also demonstrate that the observed PARK2-BECN1 interaction is functionally important. Measurements of the level of MFN2 (mitofusin 2), a PARK2 substrate, demonstrate that depletion of BECN1 prevents PARK2 translocation-induced MFN2 ubiquitination and loss. BECN1 depletion also rescues the MFN2 loss-induced suppression of mitochondrial fusion. In sum, our results demonstrate that BECN1 interacts with PARK2 and regulates PARK2 translocation to mitochondria as well as PARK2-induced mitophagy prior to autophagosome formation.


Mouse Models of Mental Illness and Neurological Disease: Huntington s Disease
Miriam Hickey, Nicholas Franich, Vera Medvedeva, and Marie-Françoise Chesselet
Elsevier



Striatal atrophy and dendritic alterations in a knock-in mouse model of Huntington's disease
Renata P. Lerner, Luz del Carmen G. Trejo Martinez, Chunni Zhu, Marie-Françoise Chesselet, and Miriam A. Hickey
Elsevier BV



Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease
Miriam A Hickey, Chunni Zhu, Vera Medvedeva, Renata P Lerner, Stefano Patassini, Nicholas R Franich, Panchanan Maiti, Sally A Frautschy, Scott Zeitlin, Michael S Levine,et al.
Springer Science and Business Media LLC
Abstract Backgound No disease modifying treatment currently exists for Huntington's disease (HD), a fatal neurodegenerative disorder characterized by the formation of amyloid-like aggregates of the mutated huntingtin protein. Curcumin is a naturally occurring polyphenolic compound with Congo red-like amyloid binding properties and the ability to cross the blood brain barrier. CAG140 mice, a knock-in (KI) mouse model of HD, display abnormal aggregates of mutant huntingtin and striatal transcriptional deficits, as well as early motor, cognitive and affective abnormalities, many months prior to exhibiting spontaneous gait deficits, decreased striatal volume, and neuronal loss. We have examined the ability of life-long dietary curcumin to improve the early pathological phenotype of CAG140 mice. Results KI mice fed a curcumin-containing diet since conception showed decreased huntingtin aggregates and increased striatal DARPP-32 and D1 receptor mRNAs, as well as an amelioration of rearing deficits. However, similar to other antioxidants, curcumin impaired rotarod behavior in both WT and KI mice and climbing in WT mice. These behavioral effects were also noted in WT C57Bl/6 J mice exposed to the same curcumin regime as adults. However, neither locomotor function, behavioral despair, muscle strength or food utilization were affected by curcumin in this latter study. The clinical significance of curcumin's impairment of motor performance in mice remains unclear because curcumin has an excellent blood chemistry and adverse event safety profile, even in the elderly and in patients with Alzheimer's disease. Conclusion Together with this clinical experience, the improvement in several transgene-dependent parameters by curcumin in our study supports a net beneficial effect of dietary curcumin in HD.


Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease
Miriam A. Hickey, Chunni Zhu, Vera Medvedeva, Nicholas R. Franich, Michael S. Levine, and Marie-Françoise Chesselet
Elsevier BV



A critical window of CAG repeat-length correlates with phenotype severity in the r6/2 mouse model of Huntington's disease
Damian M. Cummings, Yasaman Alaghband, Miriam A. Hickey, Prasad R. Joshi, S. Candice Hong, Chunni Zhu, Timothy K. Ando, Véronique M. André, Carlos Cepeda, Joseph B. Watson,et al.
American Physiological Society
The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ∼150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse relationship in human HD between CAG repeat length and age at onset and to a degree, the direct relationship with severity of disease, we have investigated the effect of altered CAG repeat length. Four lines, carrying ∼110, ∼160, ∼210, and ∼310 CAG repeats, were examined using a battery of tests designed to assess the basic R6/2 phenotype. These included electrophysiological properties of striatal medium-sized spiny neurons, motor activity, inclusion formation, and protein expression. The results showed an unpredicted, inverted “U-shaped” relationship between CAG repeat length and phenotype; increasing the CAG repeat length from 110 to 160 exacerbated the R6/2 phenotype, whereas further increases to 210 and 310 CAG repeats greatly ameliorated the phenotype. These findings demonstrate that the expected relationship between CAG repeat length and disease severity observed in humans is lost in the R6/2 mouse model and highlight the importance of CAG repeat-length determination in preclinical drug trials that use this model.


Behavioral assessment of genetic mouse models of Huntington's disease
Miriam A. Hickey and Marie-Françoise Chesselet
Humana Press



Mouse Models of Mental Illness and Neurological Disease: Huntington s Disease
Miriam Hickey, Nicholas Franich, Vera Medvedeva, and Marie-Françoise Chesselet
Elsevier

RECENT SCHOLAR PUBLICATIONS

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 Gujnsson, ...
Experimental Neurology 385, 115099 2025



Enhancing Medical Science Engagement through International Research Exchange: Objectives, Activities, and Outcomes
M Jurgenson, A Garcia Llorca, A Sarv, T Eysteinsson, MA Hickey
bioRxiv, 2025.02. 26.640317 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



Levodopa impairs lysosomal function in sensory neurons in vitro
OJ Olaoye, AE Aksoy, SV Hyytiinen, AA Narits, MA Hickey
Biology 13 (11), 893 2024



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



No Evidence of Sensory Neuropathy in a Traditional Mouse Model of Idiopathic Parkinson’s Disease
M Faisal, A Rusetskaya, L Vli, P Taba, A Minajeva, MA Hickey
Cells 13 (10), 799 2024



Research data for Early trigeminal and sensory impairment and lysosomal dysfunction in accurate models of Wolfram syndrome
M Hickey
University of Tartu 2024



Levodopa impairs lysosomal function in sensory neurons in vitro
M Hickey
University of Tartu 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



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



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



Early intervention and lifelong treatment with GLP1 receptor agonist liraglutide in a wolfram syndrome rat model with an emphasis on visual neurodegeneration, sensorineural
T Jagome, K Seppa, R Reimets, M Pastak, M Plaas, MA Hickey, ...
Cells 10 (11), 3193 2021



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



Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural
T Jagome, K Seppa, R Reimets, M Pastak, M Plaas, MA Hickey, ...
s Note: MDPI stays neutral with regard to jurisdictional claims in published 2021



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



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



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



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 Jagome, I Heinla, ...
Scientific Reports 9 (1), 5457 2019



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), e99384 2019



Magnetic resonance imaging of the brain in a rat model of Wolfram syndrome
A Shirinskaya, M Nigu, I Heinla, M Plaas, MA Hickey, A Kaasik
SCIENCE4HEALTH 2019. Клинические и теоретические аспекты современной 2019

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
Citations: 254



Apoptosis in Huntington's disease
MA Hickey, MF Chesselet
Progress in Neuro-Psychopharmacology and Biological Psychiatry 27 (2), 255-265 2003
Citations: 253



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
Citations: 243



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
Citations: 156



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
Citations: 146



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
Citations: 143



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
Citations: 137



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), 2433-2445 2010
Citations: 135



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
Citations: 134



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), e99384 2019
Citations: 118



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
Citations: 117



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
Citations: 97



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
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
Citations: 85



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
Citations: 64



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 Jagome, I Heinla, ...
Scientific Reports 9 (1), 5457 2019
Citations: 62



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 Jagome, M Toots, T Koppel, T Vallisoo, ...
Scientific reports 7 (1), 10220 2017
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
Citations: 55



Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease
MA Hickey, C Zhu, V Medvedeva, NR Franich, MS Levine, MF Chesselet
Molecular and Cellular Neuroscience 49 (2), 149-157 2012
Citations: 52



Rescuing the Corticostriatal Synaptic Disconnection in the R6/2 Mouse Model of Huntington's Disease: Exercise, Adenosine Receptors and Ampakines.
C Cepeda, DM Cummings, MA Hickey, M Kleiman-Weiner, JY Chen, ...
PLoS Currents Huntington Disease 2 2010
Citations: 52