Browsing by Subject "Huntington's disease"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Mild Cognitive Impairment as an Early Landmark in Huntington's Disease
    (Frontiers Media, 2021-07-07) Zhang, Ying; Zhou, Junyi; Gehl, Carissa R.; Long, Jeffrey D.; Johnson, Hans; Magnotta, Vincent A.; Sewell, Daniel; Shannon, Kathleen; Paulsen, Jane S.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    As one of the clinical triad in Huntington's disease (HD), cognitive impairment has not been widely accepted as a disease stage indicator in HD literature. This work aims to study cognitive impairment thoroughly for prodromal HD individuals with the data from a 12-year observational study to determine whether Mild Cognitive Impairment (MCI) in HD gene-mutation carriers is a defensible indicator of early disease. Prodromal HD gene-mutation carriers evaluated annually at one of 32 worldwide sites from September 2002 to April 2014 were evaluated for MCI in six cognitive domains. Linear mixed-effects models were used to determine age-, education-, and retest-adjusted cut-off values in cognitive assessment for MCI, and then the concurrent and predictive validity of MCI was assessed. Accelerated failure time (AFT) models were used to determine the timing of MCI (single-, two-, and multiple-domain), and dementia, which was defined as MCI plus functional loss. Seven hundred and sixty-eight prodromal HD participants had completed all six cognitive tasks, had MRI, and underwent longitudinal assessments. Over half (i.e., 54%) of the participants had MCI at study entry, and half of these had single-domain MCI. Compared to participants with intact cognitive performances, prodromal HD with MCI had higher genetic burden, worsened motor impairment, greater brain atrophy, and a higher likelihood of estimated HD onset. Prospective longitudinal study of those without MCI at baseline showed that 48% had MCI in subsequent visits and data visualization suggested that single-domain MCI, two-domain MCI, and dementia represent appropriate cognitive impairment staging for HD gene-mutation carriers. Findings suggest that MCI represents an early landmark of HD and may be a sensitive enrichment variable or endpoint for prodromal clinical trials of disease modifying therapeutics.
  • Thumbnail Image
    Item
    Oxidative metabolism and Ca2+ handling in isolated brain mitochondria and striatal neurons from R6/2 mice, a model of Huntington's disease
    (Oxford University Press, 2016-07-01) Hamilton, James; Pellman, Jessica J.; Brustovetsky, Tatiana; Harris, Robert A.; Brustovetsky, Nickolay; Pharmacology and Toxicology, School of Medicine
    Alterations in oxidative metabolism and defects in mitochondrial Ca2+ handling have been implicated in the pathology of Huntington's disease (HD), but existing data are contradictory. We investigated the effect of human mHtt fragments on oxidative metabolism and Ca2+ handling in isolated brain mitochondria and cultured striatal neurons from the R6/2 mouse model of HD. Non-synaptic and synaptic mitochondria isolated from the brains of R6/2 mice had similar respiratory rates and Ca2+ uptake capacity compared with mitochondria from wild-type (WT) mice. Respiratory activity of cultured striatal neurons measured with Seahorse XF24 flux analyzer revealed unaltered cellular respiration in neurons derived from R6/2 mice compared with neurons from WT animals. Consistent with the lack of respiratory dysfunction, ATP content of cultured striatal neurons from R6/2 and WT mice was similar. Mitochondrial Ca2+ accumulation was also evaluated in cultured striatal neurons from R6/2 and WT animals. Our data obtained with striatal neurons derived from R6/2 and WT mice show that both glutamate-induced increases in cytosolic Ca2+ and subsequent carbonilcyanide p-triflouromethoxyphenylhydrazone-induced increases in cytosolic Ca2+ were similar between WT and R6/2, suggesting that mitochondria in neurons derived from both types of animals accumulated comparable amounts of Ca2+ Overall, our data argue against respiratory deficiency and impaired Ca2+ handling induced by human mHtt fragments in both isolated brain mitochondria and cultured striatal neurons from transgenic R6/2 mice.
  • Thumbnail Image
    Item
    Oxidative metabolism and Ca2+ handling in striatal mitochondria from YAC128 mice, a model of Huntington's disease
    (Elsevier, 2017-10) Hamilton, James; Brustovetsky, Tatiana; Brustovetsky, Nickolay; Pharmacology and Toxicology, School of Medicine
    The mechanisms implicated in the pathology of Huntington's disease (HD) remain not completely understood, although dysfunction of mitochondrial oxidative metabolism and Ca2+ handling have been suggested as contributing factors. However, in our previous studies with mitochondria isolated from the whole brains of HD mice, we found no evidence for defects in mitochondrial respiration and Ca2+ handling. In the present study, we used the YAC128 mouse model of HD to evaluate the effect of mHtt on respiratory activity and Ca2+ uptake capacity of mitochondria isolated from the striatum, the most vulnerable brain region in HD. Isolated, Percoll-gradient purified striatal mitochondria from YAC128 mice were free of cytosolic and ER contaminations, but retained attached mHtt. Both nonsynaptic and synaptic striatal mitochondria isolated from early symptomatic 2-month-old YAC128 mice had similar respiratory rates and Ca2+ uptake capacities compared with mitochondria from wild-type FVB/NJ mice. Consistent with the lack of difference in mitochondrial respiration, we found that the expression of several nuclear-encoded proteins in striatal mitochondria was similar between wild-type and YAC128 mice. Taken together, our data demonstrate that mHtt does not alter respiration and Ca2+ uptake capacity in striatal mitochondria isolated from YAC128 mice, suggesting that respiratory defect and Ca2+ uptake deficiency most likely do not contribute to striatal pathology associated with HD.
  • Thumbnail Image
    Item
    Oxidative metabolism and mitochondrial calcium handling in mouse models of Huntington's Disease
    (2017-08-23) Hamilton, James M.; Brustovetsky, Nickolay; Cummins, Theodore R.; Hudmon, Andy; Robling, Alexander G.; Sullivan, William J., Jr.
    Huntington’s disease (HD) is an autosomal dominantly inherited, fatal neurodegenerative disorder for which there is no cure. HD is clinically characterized by progressively worsening motor, cognitive, and psychiatric disturbances. Currently available therapeutics for HD only treat symptoms, but do not address underlying disease pathology. HD pathogenesis is linked to a mutation in the huntingtin gene, which encodes a protein called huntingtin (Htt) that is normally involved in a variety of cellular processes. In healthy individuals, the N-terminus of huntingtin possesses a polyglutamine stretch containing less than 35 glutamines, however, the mutated huntingtin protein (mHtt) has an elongated polyglutamine tract that correlates with the development of HD. The mechanism of deleterious action by mHtt is unknown, but a major hypothesis postulates that mHtt may cause mitochondrial dysfunction. However, the data regarding involvement of mitochondrial impairment in HD pathology are contradictory. Some investigators previously reported, for example, that mHtt suppresses mitochondrial respiratory activity and decreases mitochondrial Ca2+ uptake capacity. However, other investigators found increased respiratory activity and augmented mitochondrial Ca2+ uptake capacity. We used transgenic mouse models of HD to investigate the effect of full-length and fragments of mHtt on oxidative metabolism and Ca2+ handling using a combination of isolated mitochondria, primary neurons, and whole-animal metabolic measurements. We evaluated the effect of full-length mHtt on isolated mitochondria and primary neurons from YAC128 mice. We found no alteration in respiratory activity or Ca2+ uptake capacity, indicative of mitochondrial damage, between mitochondria or neurons from YAC128 mice compared to wild-type (WT) mice. Furthermore, we measured whole animal oxidative metabolism and physical activity level and found that YAC128 mice do not display any decline in metabolic and physical activity. Although full-length mHtt expressing YAC128 mice may be a more faithful genetic recapitulation of HD, data suggests mHtt fragments may be more toxic. To assess the effect of mHtt fragments, we used isolated brain mitochondria and primary striatal neurons from the R6/2 mouse model and found no significant impairment in respiration or Ca2+ handling. Thus, our data strongly support the hypothesis that mHtt does not alter mitochondrial functions assessed either with isolated mitochondria, primary neurons, or whole animals.
  • Thumbnail Image
    Item
    Regulation of neuronal calcium homeostasis in Huntington's
    (2015-07-28) Pellman, Jessica J.; Brustovetsky, Nickolay; Cummins, Theodore R.; Jerde, Travis J.; Khanna, Rajesh; Vasko, Michael R.
    Huntington’s Disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder. There is no cure for HD and the existing therapies only alleviate HD symptoms without eliminating the cause of this neuropathology. HD is linked to a mutation in the huntingtin gene, which results in an elongation of the poly-glutamine stretch in the huntingtin protein (Htt). A major hypothesis is that mutant Htt (mHtt) leads to aberrant Ca2+ homeostasis in affected neurons. This may be caused by increased Ca2+ influx into the cell via the N-methyl-Daspartate (NMDA)-subtype of glutamate receptors. The contribution of two major Ca2+ removal mechanisms, mitochondria and plasmalemmal Na+/Ca2+ exchangers (NCX), in neuronal injury in HD remains unclear. We investigated Ca2+ uptake capacity in isolated synaptic (neuronal) and nonsynaptic mitochondria from the YAC128 mouse model of HD. We found that both Htt and mHtt bind to brain mitochondria and the amount of mitochondriabound mHtt correlates with increased mitochondrial Ca2+ uptake capacity. Mitochondrial Ca2+ accumulation was not impaired in striatal neurons from YAC128 mice. We also found that expression of the NCX1 isoform is increased with age in striatum from YAC128 mice compared to striatum from wild-type mice. Interestingly, mHtt and Htt bind to the NCX3 isoform but not to NCX1. NCX3 expression remains unchanged. To further investigate Ca2+ homeostasis modulation, we examined the role of collapsin response mediator protein 2 (CRMP2) in wild-type neurons. CRMP2 is viewed as an axon guidance protein, but has been found to be involved in Ca2+ signaling. We found that CRMP2 interacts with NMDA receptors (NMDAR) and disrupting this interaction decreases NMDAR activity. CRMP2 also interacts with and regulates NCX3, resulting in NCX3 internalization and decreased activity. Augmented mitochondrial Ca2+ uptake capacity and an increased expression of NCX1 in the presence of mHtt suggest a compensatory reaction in response to increased Ca2+ influx into the cell. The role of NCX warrants further investigation in HD. The novel interactions of CRMP2 with NMDAR and NCX3 provide additional insight into the complexity of Ca2+ homeostasis regulation in neurons and may also be important in HD neuropathology.