IU Indianapolis ScholarWorks :: Browsing by Subject "Neurodegeneration"

Browsing by Subject "Neurodegeneration"

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The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic
(Elsevier, 2020-02) Gentry, Matthew S.; Afawi, Zaid; Armstrong, Dustin D.; Delgado-Escueta, Antonio; Goldberg, Y. Paul; Grossman, Tamar R.; Guinovart, Joan J.; Harris, Frank; Hurley, Thomas D.; Michelucci, Roberto; Minassian, Berge A.; Sanz, Pascual; Worby, Carolyn A.; Serratosa, Jose M.; Biochemistry and Molecular Biology, School of Medicine
Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study.
Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein
(Society for Neuroscience, 2002-11) Allen, Bridget; Ingram, Esther; Takao, Masaki; Smith, Michael J.; Jakes, Ross; Virdee, Kanwar; Yoshida, Hirotaka; Holzer, Max; Craxton, Molly; Emson, Piers C.; Atzori, Cristiana; Migheli, Antonio; Crowther, R. Anthony; Ghetti, Bernardino; Spillantini, Maria Grazia; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies. Perchloric acid-soluble tau was also phosphorylated at many sites, with the notable exception of serine 214. In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons. No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau.
Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease
(National Academy of Sciences, 2017-12-05) Rasmussen, Jay; Mahler, Jasmin; Beschorner, Natalie; Kaeser, Stephan A.; Häsler, Lisa M.; Baumann, Frank; Nyström, Sofie; Portelius, Erik; Blennow, Kaj; Lashley, Tammaryn; Fox, Nick C.; Sepulveda-Falla, Diego; Glatzel, Markus; Oblak, Adrian L.; Ghetti, Bernardino; Nilsson, K. Peter R.; Hammarström, Per; Staufenbiel, Matthias; Walker, Lary C.; Jucker, Mathias; Pathology and Laboratory Medicine, School of Medicine
The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.
Cdk5 activity in the brain - multiple paths of regulation
(The Company of Biologists, 2014-06-01) Shah, Kavita; Lahiri, Debomoy; Department of Medical and Molecular Genetics, IU School of Medicine
Cyclin dependent kinase-5 (Cdk5), a family member of the cyclin-dependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5. © 2014. Published by The Company of Biologists Ltd.
Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation
(National Academy of Sciences, 2017-01-17) McEwan, William A.; Falcon, Benjamin; Vaysburd, Marina; Clift, Dean; Oblak, Adrian L.; Ghetti, Bernardino; Goedert, Michel; James, Leo C.; Pathology and Laboratory Medicine, School of Medicine
Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.
Effects of coadministration of D-Napvsipq [NAP] and D-Sallrsipa [SAL] on spatial learning after developmental alcohol exposure
(2013) Wagner, Jennifer Lynne; Goodlett, Charles R.; Neal-Beliveau, Bethany S.; Grahame, Nicholas J.; Powley, T. L. (Terry L.)
Despite warnings about the dangers of drinking during pregnancy, little progress has been made in reducing alcohol drinking among women of childbearing age. Even after the recognition of pregnancy, 15% of women continue to drink, 3% of which admit to binge drinking. Because we cannot stop women from drinking during pregnancy, and many children with fetal alcohol spectrum disorders (FASD) are adopted, there is a significant need to develop postnatal interventions that can improve the long-term outcome of children adversely affected by prenatal alcohol exposure. This thesis aims to evaluate one promising new treatment in the rehabilitation or rescue of specific learning deficits long after the damage has occurred. The treatment evaluated herein (40µg D-NAP + 40µg D-SAL) has long been used in the prevention of the detrimental effects of long-term and binge-like alcohol exposures in rodent models of fetal alcohol syndrome and FASD. Until recently this peptide treatment had only been shown to be effective in preventing some of the consequences of alcohol exposure when administered concurrently with the prenatal alcohol exposure. A recent report by Incerti and colleagues (2010c), however, reported that these peptides could completely reverse a profound spatial learning deficit induced by one episode of a heavy binge-like alcohol exposure (5.9g.kg in a single intraperitoneal injection) on gestational day 8 (G8) in C57BL/6 mice. In that report, the peptide treatment was administered starting in late adolescence, beginning three days prior to and throughout water maze training, and the profound deficits in their alcohol-placebo group were completely eliminated in the alcohol-peptide group. There are currently no FDA-approved treatments for FASD. An effective treatment for the cognitive and behavioral dysfunctions suffered by the 1% of people born today could potentially improve the lives of millions of children and adults. The first aim of this thesis was to determine whether the peptide treatment could reverse the significant spatial learning deficits we have demonstrated in adult C57BL/6 mice given high-dose binge-like alcohol exposure (2.5 g/kg in each of two intraperitoneal injections separated by two hours) on postnatal day (P)7. When administered three days prior to and throughout water maze testing (P67-76), the peptide treatment had no effect on spatial learning. The second aim sought to determine whether the same peptide treatment could reverse water maze spatial learning deficits in G8 binge-like exposure models, as reported by Incerti et al. (2010c). For this analysis, the first study used a different binge-like alcohol exposure model that is more commonly used than that employed by the Incerti et al. (2010c) study, namely administration of 2.8g/kg in each of two intraperitoneal injections separated by four hours (Sulik et al., 1981). This model has been shown to produce high peak blood alcohol concentrations and neuroanatomical aberrations in the hippocampal formation and septal regions (Parnell et al., 2009), which have been implicated in learning and memory. Surprisingly, this G8 binge-like alcohol exposure failed to produce a spatial learning deficit, undermining the usefulness of this model in evaluating the peptide effects. In direct contrast to the outcomes of Incerti et al. (2010c), the G8 Webster alcohol exposure was also unable to produce any deficits in acquisition of spatial learning in the Morris water maze. Surprisingly, neither of the heavy binge-like alcohol exposures on G8 were able to produce spatial learning deficits in the Morris water maze. The binge-like alcohol exposure on P7 did yield the expected spatial learning deficit, but the peptide treatment was unsuccessful in recovering water maze learning. These findings fail to support oral administration of 40µg D-NAP and 40 µg D-SAL as a potential therapy for postnatal alcohol-induced spatial learning deficits in adult mice.
In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls
(Springer Nature, 2018-04) Louis, Elan D.; Hernandez, Nora; Dyke, Jonathan P.; Ma, Ruoyun E.; Dydak, Ulrike; Radiology and Imaging Sciences, School of Medicine
Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. CONTROLS: One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed.
Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration
(Frontiers Media, 2019-12-11) Muhoberac, Barry B.; Vidal, Ruben; Chemistry and Chemical Biology, School of Science
Cellular growth, function, and protection require proper iron management, and ferritin plays a crucial role as the major iron sequestration and storage protein. Ferritin is a 24 subunit spherical shell protein composed of both light (FTL) and heavy chain (FTH1) subunits, possessing complimentary iron-handling functions and forming three-fold and four-fold pores. Iron uptake through the three-fold pores is well-defined, but the unloading process somewhat less and generally focuses on lysosomal ferritin degradation although it may have an additional, energetically efficient pore mechanism. Hereditary Ferritinopathy (HF) or neuroferritinopathy is an autosomal dominant neurodegenerative disease caused by mutations in the FTL C-terminal sequence, which in turn cause disorder and unraveling at the four-fold pores allowing iron leakage and enhanced formation of toxic, improperly coordinated iron (ICI). Histopathologically, HF is characterized by iron deposition and formation of ferritin inclusion bodies (IBs) as the cells overexpress ferritin in an attempt to address iron accumulation while lacking the ability to clear ferritin and its aggregates. Overexpression and IB formation tax cells materially and energetically, i.e., their synthesis and disposal systems, and may hinder cellular transport and other spatially dependent functions. ICI causes cellular damage to proteins and lipids through reactive oxygen species (ROS) formation because of high levels of brain oxygen, reductants and metabolism, taxing cellular repair. Iron can cause protein aggregation both indirectly by ROS-induced protein modification and destabilization, and directly as with mutant ferritin through C-terminal bridging. Iron release and ferritin degradation are also linked to cellular misfunction through ferritinophagy, which can release sufficient iron to initiate the unique programmed cell death process ferroptosis causing ROS formation and lipid peroxidation. But IB buildup suggests suppressed ferritinophagy, with elevated iron from four-fold pore leakage together with ROS damage and stress leading to a long-term ferroptotic-like state in HF. Several of these processes have parallels in cell line and mouse models. This review addresses the roles of ferritin structure and function within the above-mentioned framework, as they relate to HF and associated disorders characterized by abnormal iron accumulation, protein aggregation, oxidative damage, and the resulting contributions to cumulative cellular stress and death.
Lithium alters expression of RNAs in a type-specific manner in differentiated human neuroblastoma neuronal cultures, including specific genes involved in Alzheimer’s disease
(Nature Research, 2019-12-04) Maloney, Bryan; Balaraman, Yokesh; Liu, Yunlong; Chopra, Nipun; Edenberg, Howard J.; Kelsoe, John; Nurnberger, John I.; Lahiri, Debomoy K.; Psychiatry, School of Medicine
Lithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple nervous system disorders, including Alzheimer’s disease (AD). While perturbation of RNA levels by Li has been previously reported, its effects on the whole transcriptome has been given little attention. We, therefore, sought to determine comprehensive effects of Li treatment on RNA levels. We cultured and differentiated human neuroblastoma (SK-N-SH) cells to neuronal cells with all-trans retinoic acid (ATRA). We exposed cultures for one week to lithium chloride or distilled water, extracted total RNA, depleted ribosomal RNA and performed whole-transcriptome RT-sequencing. We analyzed results by RNA length and type. We further analyzed expression and protein interaction networks between selected Li-altered protein-coding RNAs and common AD-associated gene products. Lithium changed expression of RNAs in both non-specific (inverse to sequence length) and specific (according to RNA type) fashions. The non-coding small nucleolar RNAs (snoRNAs) were subject to the greatest length-adjusted Li influence. When RNA length effects were taken into account, microRNAs as a group were significantly less likely to have had levels altered by Li treatment. Notably, several Li-influenced protein-coding RNAs were co-expressed or produced proteins that interacted with several common AD-associated genes and proteins. Lithium’s modification of RNA levels depends on both RNA length and type. Li activity on snoRNA levels may pertain to bipolar disorders while Li modification of protein coding RNAs may be relevant to AD.
Luminescent conjugated oligothiophenes distinguish between α-synuclein assemblies of Parkinson’s disease and multiple system atrophy
(BMC, 2019-12-03) Klingstedt, Therése; Ghetti, Bernardino; Holton, Janice L.; Ling, Helen; Nilsson, K. Peter R.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
Synucleinopathies [Parkinson’s disease with or without dementia, dementia with Lewy bodies and multiple system atrophy] are neurodegenerative diseases that are defined by the presence of filamentous α-synuclein inclusions. We investigated the ability of luminescent conjugated oligothiophenes to stain the inclusions of Parkinson’s disease and multiple system atrophy. They stained the Lewy pathology of Parkinson’s disease and the glial cytoplasmic inclusions of multiple system atrophy. Spectral analysis of HS-68-stained inclusions showed a red shift in multiple system atrophy, but the difference with Parkinson’s disease was not significant. However, when inclusions were double-labelled for HS-68 and an antibody specific for α-synuclein phosphorylated at S129, they could be distinguished based on colour shifts with blue designated for Parkinson’s disease and red for multiple system atrophy. The inclusions of Parkinson’s disease and multiple system atrophy could also be distinguished using fluorescence lifetime imaging. These findings are consistent with the presence of distinct conformers of assembled α-synuclein in Parkinson’s disease and multiple system atrophy.

Browsing by Subject "Neurodegeneration"

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