SIRT2 Ablation Has No Effect on Tubulin Acetylation in Brain, Cholesterol Biosynthesis or the Progression of Huntington's Disease Phenotypes In Vivo

AbstractSupplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

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SREBP2 delivery to striatal astrocytes normalizes transcription of cholesterol biosynthesis genes and ameliorates pathological features in Huntington’s Disease

10.1101/2020.11.23.393793 ◽

2020 ◽

Author(s):

Giulia Birolini ◽

Gianluca Verlengia ◽

Francesca Talpo ◽

Claudia Maniezzi ◽

Lorena Zentilin ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Nuclear Translocation ◽

Regulatory Element ◽

Cholesterol Biosynthesis ◽

Biosynthesis Pathway ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Cholesterol Biosynthesis Pathway

AbstractBrain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington’s Disease (HD). One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway.Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the N-terminal fragment of human SREBP2 (hSREBP2).Robust hSREBP2 expression in striatal glial cells in HD mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed Drd2 transcript levels decline, cleared muHTT aggregates and attenuated behavioral deficits. We conclude that glial SREBP2 participates in HD brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of HD.

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Faculty Opinions recommendation of Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732609529.793548926 ◽

2018 ◽

Author(s):

David Schaffer ◽

Maroof Adil

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Patient ◽

Striatal Neurons ◽

Disease Phenotypes

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In Vivo Expression of Reprogramming Factor OCT4 Ameliorates Myelination Deficits and Induces Striatal Neuroprotection in Huntington’s Disease

Genes ◽

10.3390/genes12050712 ◽

2021 ◽

Vol 12 (5) ◽

pp. 712

Author(s):

Ji-Hea Yu ◽

Bae-Geun Nam ◽

Min-Gi Kim ◽

Soonil Pyo ◽

Jung-Hwa Seo ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cell Fate ◽

Gabaergic Neurons ◽

Oligodendrocyte Progenitor Cells ◽

Adeno Associated Virus ◽

In Vivo Expression ◽

Transcription Factor 4 ◽

Phosphate Buffered Saline

White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington’s disease (HD). This study investigated the effects of in vivo expression of reprogramming factor octamer-binding transcription factor 4 (OCT4) on neural stem cell (NSC) niche activation in the subventricular zone (SVZ) and induction of cell fate specific to the microenvironment of HD. R6/2 mice randomly received adeno-associated virus 9 (AAV9)-OCT4, AAV9-Null, or phosphate-buffered saline into both lateral ventricles at 4 weeks of age. The AAV9-OCT4 group displayed significantly improved behavioral performance compared to the control groups. Following AAV9-OCT4 treatment, the number of newly generated NSCs and oligodendrocyte progenitor cells (OPCs) significantly increased in the SVZ, and the expression of OPC-related genes and glial cell-derived neurotrophic factor (GDNF) significantly increased. Further, amelioration of myelination deficits in the corpus callosum was observed through electron microscopy and magnetic resonance imaging, and striatal DARPP32+ GABAergic neurons significantly increased in the AAV9-OCT4 group. These results suggest that in situ expression of the reprogramming factor OCT4 in the SVZ induces OPC proliferation, thereby attenuating myelination deficits. Particularly, GDNF released by OPCs seems to induce striatal neuroprotection in HD, which explains the behavioral improvement in R6/2 mice overexpressing OCT4.

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In vivo examination of the Pre- and postsynaptic dopamine neurons in huntington's disease

European Neuropsychopharmacology ◽

10.1016/0924-977x(96)87905-3 ◽

1996 ◽

Vol 6 ◽

pp. 130

Author(s):

N. Ginovart ◽

A. Lundin ◽

L. Farde ◽

C. Halldin ◽

C.G. Swahn ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Dopamine Neurons

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Cortical circuit alterations precede disease onset in Huntington’s disease mice

10.1101/391771 ◽

2018 ◽

Author(s):

Johanna Neuner ◽

Elena Katharina Schulz-Trieglaff ◽

Sara Gutiérrez-Ángel ◽

Fabian Hosp ◽

Matthias Mann ◽

...

Keyword(s):

Motor Cortex ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Primary Motor Cortex ◽

Disease Onset ◽

Single Neurons ◽

Two Photon ◽

Layer 2 ◽

Cortical Circuit

AbstractHuntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronicin vivotwo-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD.Significance statementFuntional alterations in the cortex are believed to play an important role in the pathogenesis of Huntington’s disease (HD). However, studies monitoring cortical activity in HD modelsin vivoat a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.

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Cerebral dopamine neurotrophic factor (CDNF) protects against quinolinic acid-induced toxicity in in vitro and in vivo models of Huntington’s disease

Scientific Reports ◽

10.1038/s41598-020-75439-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

P. Stepanova ◽

V. Srinivasan ◽

D. Lindholm ◽

M. H. Voutilainen

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Quinolinic Acid ◽

Neurotrophic Factor ◽

Striatal Neurons ◽

In Vivo Models ◽

Cerebral Dopamine Neurotrophic Factor ◽

Cerebral Dopamine

Abstract Huntington’s disease (HD) is a neurodegenerative disorder with a progressive loss of medium spiny neurons in the striatum and aggregation of mutant huntingtin in the striatal and cortical neurons. Currently, there are no rational therapies for the treatment of the disease. Cerebral dopamine neurotrophic factor (CDNF) is an endoplasmic reticulum (ER) located protein with neurotrophic factor (NTF) properties, protecting and restoring the function of dopaminergic neurons in animal models of PD more effectively than other NTFs. CDNF is currently in phase I–II clinical trials on PD patients. Here we have studied whether CDNF has beneficial effects on striatal neurons in in vitro and in vivo models of HD. CDNF was able to protect striatal neurons from quinolinic acid (QA)-induced cell death in vitro via increasing the IRE1α/XBP1 signalling pathway in the ER. A single intrastriatal CDNF injection protected against the deleterious effects of QA in a rat model of HD. CDNF improved motor coordination and decreased ataxia in QA-toxin treated rats, and stimulated the neurogenesis by increasing doublecortin (DCX)-positive and NeuN-positive cells in the striatum. These results show that CDNF positively affects striatal neuron viability reduced by QA and signifies CDNF as a promising drug candidate for the treatment of HD.

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Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

International Journal of Experimental Pathology ◽

10.1111/iep.12320 ◽

2019 ◽

Vol 100 (2) ◽

pp. 64-71

Author(s):

Olga A. Zhunina ◽

Nikita G. Yabbarov ◽

Alexander N. Orekhov ◽

Alexey V. Deykin

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease

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