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1.
J Huntingtons Dis ; 10(4): 435-454, 2021.
Article in English | MEDLINE | ID: mdl-34459410

ABSTRACT

BACKGROUND: The Huntingtin (HTT) N-terminal domains encoded by Huntingtin's (HTT) exon 1 consist of an N17 domain, the polyglutamine (polyQ) stretch and a proline-rich region (PRR). These domains are conserved in mammals and have been hypothesized to modulate HTT's functions in the developing and adult CNS, including DNA damage repair and autophagy. OBJECTIVE: This study longitudinally characterizes the in vivo consequences of deleting the murine Htt N-terminal domains encoded by Htt exon 1. METHODS: Knock-in mice with a deletion of Htt exon 1 sequences (HttΔE1) were generated and bred into the C57BL/6J congenic genetic background. Their behavior, DNA damage response, basal autophagy, and glutamatergic synapse numbers were evaluated. RESULTS: Progeny from HttΔE1/+ intercrosses are born at the expected Mendelian frequency but with a distorted male to female ratio in both the HttΔE1/ΔE1 and Htt+/+ offspring. HttΔE1/ΔE1 adults exhibit a modest deficit in accelerating rotarod performance, and an earlier increase in cortical and striatal DNA damage with elevated neuronal pan-nuclear 53bp1 levels compared to Htt+/+ mice. However, a normal response to induced DNA damage, normal levels of basal autophagy markers, and no significant differences in corticocortical, corticostriatal, thalamocortical, or thalamostriatal synapses numbers were observed compared to controls. CONCLUSION: Our results suggest that deletion of the Htt N-terminus encoded by the Htt exon 1 does not affect Htt's critical role during embryogenesis, but instead, may have a modest effect on certain motor tasks, basal levels of DNA damage in the brain, and Htt function in the testis.


Subject(s)
Huntington Disease , Animals , Brain/metabolism , Disease Models, Animal , Exons/genetics , Female , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Huntington Disease/genetics , Male , Mice , Mice, Inbred C57BL
2.
PLoS One ; 14(7): e0219691, 2019.
Article in English | MEDLINE | ID: mdl-31306446

ABSTRACT

Alzheimer disease (AD) is a neurodegenerative disorder characterized by pathological hallmarks of neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid ß (Aß), a cleavage fragment of amyloid precursor protein (APP). Enhanced neuronal activity and seizure events are frequently observed in AD, and elevated synaptic activity promotes Aß production. However, the mechanisms that link synaptic hyperactivity to APP processing and AD pathogenesis are not well understood. We previously found that Polo-like kinase 2 (Plk2), a homeostatic repressor of neuronal overexcitation, promotes APP ß-processing in vitro. Here, we report that Plk2 stimulates Aß production in vivo, and that Plk2 levels are elevated in a spatiotemporally regulated manner in brains of AD mouse models and human AD patients. Genetic disruption of Plk2 kinase function reduces plaque deposits and activity-dependent Aß production. Furthermore, pharmacological Plk2 inhibition hinders Aß formation, synapse loss, and memory decline in an AD mouse model. Thus, Plk2 links synaptic overactivity to APP ß-processing, Aß production, and disease-relevant phenotypes in vivo, suggesting that Plk2 may be a potential target for AD therapeutics.


Subject(s)
Alzheimer Disease/enzymology , Amyloid beta-Peptides/metabolism , Neurons/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/physiology , Animals , Disease Models, Animal , Female , Hippocampus/enzymology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plaque, Amyloid/pathology , Synapses/metabolism
3.
J Huntingtons Dis ; 7(2): 137-150, 2018.
Article in English | MEDLINE | ID: mdl-29843246

ABSTRACT

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disorder associated with aging, caused by an expanded polyglutamine (polyQ) repeat within the Huntingtin (HTT) protein. In HD, degeneration of the striatum and atrophy of the cortex are observed while cerebellum is less affected. OBJECTIVE: To test the hypothesis that HTT protein levels decline with age, which together with HTT mutation could influence disease progression. METHODS: Using whole brain cell lysates, a unique method of SDS-PAGE and western analysis was used to quantitate HTT protein, which resolves as a monomer and as a high molecular weight species that is modulated by the presence of transglutaminase 2. HTT levels were measured in striatum, cortex and cerebellum in congenic homozygous Q140 and HdhQ150 knock-in mice and WT littermate controls. RESULTS: Mutant HTT in both homozygous knock-in HD mouse models and WT HTT in control striatal and cortical tissues significantly declined in a progressive manner over time. Levels of mutant HTT in HD cerebellum remained high during aging. CONCLUSIONS: A general decline in mutant HTT levels in striatum and cortex is observed that may contribute to disease progression in homozygous knock-in HD mouse models through reduction of HTT function. In cerebellum, sustained levels of mutant HTT with aging may be protective to this tissue which is less overtly affected in HD.


Subject(s)
Corpus Striatum/metabolism , Disease Progression , Huntingtin Protein/metabolism , Huntington Disease/metabolism , Aging , Animals , Cerebellum/metabolism , Cerebral Cortex/metabolism , Disease Models, Animal , Female , Gene Knock-In Techniques , Homozygote , Huntingtin Protein/genetics , Male , Mice, Inbred C57BL , Mutant Proteins/genetics , Mutant Proteins/metabolism
4.
Future Neurol ; 13(1): 13-21, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29379396

ABSTRACT

Brain activity levels are tightly regulated to minimize imbalances in activity state. Deviations from the normal range of activity are deleterious and often associated with neurological disorders. To maintain optimal levels of activity, regulatory mechanisms termed homeostatic synaptic plasticity establish desired 'set points' for neural activity, monitor the network for deviations from the set point and initiate compensatory responses to return activity to the appropriate level that permits physiological function [1,2]. We speculate that impaired homeostatic control may contribute to the etiology of various neurological disorders including epilepsy and Alzheimer's disease, two disorders that exhibit hyperexcitability as a key feature during pathogenesis. Here, we will focus on recent progress in developing homeostatic regulation of neural activity as a therapeutic tool.

5.
J Huntingtons Dis ; 6(1): 47-62, 2017.
Article in English | MEDLINE | ID: mdl-28211815

ABSTRACT

BACKGROUND: The polyglutamine (polyQ) stretch of the Huntingtin protein (HTT) in mammals is flanked by a highly conserved 17 amino acid N-terminal domain (N17), and a proline-rich region (PRR). The PRR is a binding site for many HTT-interacting proteins, and the N17 domain regulates several normal HTT functions, including HTT's ability to associate with membranes and organelles. OBJECTIVE: This study investigates the consequence of deleting mouse Huntingtin's (Htt's) N17 domain or a combination of its polyQ stretch and PRR (QP) on normal Htt function in mice. METHODS: Knock-in mice expressing versions of Htt lacking either the N17 domain (HttΔN17) or both the polyQ and PRR domains (HttΔQP) were generated, and their behavior, autophagy function, and neuropathology were evaluated. RESULTS: Homozygous and hemizygous HttΔQP/ΔQP, HttΔN17/ΔN17, HttΔQP/-, and HttΔN17/- mice were generated at the expected Mendelian frequency. HttΔQP/ΔQP mutants exhibit improvements in motor coordination compared to controls (Htt+/+). In contrast, HttΔN17/ΔN17 mutants do not exhibit any changes in motor coordination, but they do display variable changes in spatial learning that are dependent on their age at testing. Neither mutant exhibited any changes in basal autophagy in comparison to controls, but thalamostriatal synapses in the dorsal striatum of 24-month-old HttΔN17/ΔN17 mice were decreased compared to controls. CONCLUSIONS: These findings support the hypothesis that Htt's N17 and QP domains are dispensable for its critical functions during early embryonic development, but are likely more important for Htt functions in CNS development or maintenance.


Subject(s)
Brain/metabolism , Huntingtin Protein/genetics , Huntington Disease/genetics , Huntington Disease/metabolism , Neurons/metabolism , Sequence Deletion , Animals , Autophagy/physiology , Brain/growth & development , Brain/pathology , Cells, Cultured , Disease Models, Animal , Gene Knock-In Techniques , Huntingtin Protein/metabolism , Huntington Disease/pathology , Male , Maze Learning/physiology , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Neurons/pathology , Peptides/genetics , Proline/genetics , Protein Domains
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