Post-symptomatic Delivery of Brain-Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis

Sheeler, Carrie; Rosa, Juao-Guilherme; Borgenheimer, Ella; Mellesmoen, Aaron; Rainwater, Orion; Cvetanović, Marija

doi:10.1007/s12311-020-01226-3

Cited by 17 publications

(23 citation statements)

References 51 publications

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“…The restoration of BDNF-TrkB signaling we describe here for SCA6 is a promising potential therapeutic approach for multiple ataxias. Our results are consistent with previous findings that viral reintroduction of the BDNF gene rescued ataxia in Stargazer mice 12 and acute cerebellar delivery of BDNF to SCA1 ATXN1(82Q) mouse model had a similar therapeutic effect 11,46 . However, overexpression of BDNF has been associated with negative outcomes in some cases 47–49 , likely due to the complex signaling pathways that are known to be activated by BDNF.…”

Section: Discussionsupporting

confidence: 93%

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Cook

Jayabal

Sheng

et al. 2021

Preprint

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Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease resulting in motor coordination deficits and cerebellar pathology. Expression of brain-derived neurotrophic factor (BDNF) is reduced in several neurodegenerative diseases, including in post-mortem tissue from SCA6 patients. Here, we show that cerebellar BDNF levels are reduced at an early disease stage in a mouse model of SCA6 (SCA684Q/84Q). One month of voluntary exercise was sufficient to elevate BDNF expression, as well as rescue both motor coordination and cerebellar Purkinje cell firing rate deficits. A BDNF mimetic, 7,8- dihydroxyflavone (7,8-DHF) likewise improved motor coordination and reversed Purkinje cell firing rate deficits, suggesting that exercise acts via BDNF-TrkB signaling. Prolonged chronic 7,8-DHF administration rescued ataxia when treatment commenced near disease onset, but was ineffective when treatment was started late. These data suggest that 7,8-DHF, which is orally bioavailable and crosses the blood-brain barrier, is a promising therapeutic for SCA6 and argue for the importance of early intervention for SCA6.

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Section: Discussionsupporting

confidence: 93%

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Cook

Jayabal

Sheng

et al. 2021

Preprint

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“…BDNF has been shown to play key roles in brain physiology and dysfunction including neurodegenerative diseases and depression [72]. In addition to our findings in SCA1 patients and model mice, decreased BDNF in patients and in mouse models has been described in other polyQ neurodegenerative diseases such as Huntington’s disease (HD)[4][5] and SCA6 [6] [7]. Decreased BDNF has also been shown to correlate with behavioral impairments with aging, Alzheimer’s disease (AD), and Parkinson’s disease (PD) [8][9][10][11][12].…”

Section: Discussionsupporting

confidence: 57%

“…Our previous studies demonstrated that exogenous BDNF delivery during the early disease stage protected against cerebellar pathology and motor deficits in the transgenic ATXN1[82Q] model of SCA1 mice and was more beneficial then BDNF treatment at the mid-disease stage [6][7]. We extended these findings to demonstrate that exogenous BDNF significantly ameliorated motor deficits and improved strategy development in Atxn1 154 Q/ 2 Q mice.…”

Section: Discussionmentioning

confidence: 66%

“…Since previous studies have indicated the importance of early disease intervention on therapeutic efficacy, we initiated BDNF treatment at 7 weeks of age [7]. Prior to surgical implantation of Alzet pumps (delivering BDNF or aCSF vehicle), Atxn1 1 54Q/2Q mice and WT littermate controls were subjected to motor and cognitive testing as well as body weight analysis in order to determine whether Atxn1 1 54Q/2Q mice exhibited disease phenotypes and to ensure there were no differences among mice randomly assigned to BDNF or aCSF delivery.…”

Section: Resultsmentioning

confidence: 99%

“…We previously showed that chronic administration of exogenous BDNF into the lateral ventricle delayed the onset of motor deficits and development of cerebellar pathology in pre-symptomatic ATXN1[82Q] mice [6]. Further, chronic administration of exogenous BDNF ameliorated motor deficits and cerebellar pathology in symptomatic ATXN1[82Q] mice [7]. These findings from the transgenic ATXN1[82Q] mouse model support our overall hypothesis that the BDNF signaling pathway may be a therapeutic target for cerebellar pathology in SCA1.…”

Section: Introductionmentioning

confidence: 99%

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Spatial and temporal diversity of astrocyte phenotypes in Spinocerebellar ataxia type 1 mice

Rosa¹,

Hamel²,

Sheeler³

et al. 2021

Preprint

Self Cite

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Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1) and characterized by motor deficits, cognitive decline, changes in affect, and premature lethality. Due to the severe cerebellar degeneration in SCA1, the pathogenesis of Purkinje cells has been the main focus of previous studies. However, mutant ATXN1 is expressed throughout the brain, and pathology in brain regions beyond the cerebellar cortex likely contribute to the symptoms of SCA1. Here, we investigate early-stage SCA1 alterations in neurons, astrocytes, and microglia in clinically relevant brain regions including hippocampus and brain stem of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1 expressing mutant ATXN1 globally. Our results indicate shared and brain region specific astrocyte pathology early in SCA1 preceding neuronal loss. We found reduced expression of homeostatic astrocytic genes Kcnj10, Aqp4, Slc1a2 and Gja1, all of which are key for neuronal function in the hippocampus and brain stem. These gene expression changes did not correlate with classical astrogliosis. Neuronal and microglial numbers were largely unaltered at this early stage of SCA1 with the exception of cerebellar white matter, where we found significant reduction in microglial density, and the brain stem where we detected an increase in microglial cell counts. Brain-derived neurotrophic factor (BDNF) is a growth factor important for the survival and function of neurons with broad therapeutic potential for many brain diseases. We report here that BDNF expression is decreased in cerebellum and medulla of patients with SCA1. Moreover, we found that BDNF had dual effect on SCA1 and wild-type mice. Motor performance, strategy development, hippocampal neurogenesis, and expression of astrocyte homeostatic genes in the hippocampus were ameliorated in BDNF-treated SCA1 mice and further enhanced in BDNF-treated wild-type mice. On the other hand, BDNF had a negative effect on memory recall and expression of homeostatic genes in the brain stem astrocytes both in wild-type and in SCA1 mice.

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Antisense oligonucleotides targeting basal forebrain ATXN2 enhances spatial memory and ameliorates sleep deprivation‐induced fear memory impairment in mice

Ma¹,

Feng

Wei

et al. 2023

Brain and Behavior

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Introduction Regulation of brain‐derived neurotrophic factor (BDNF) in the basal forebrain ameliorates sleep deprivation‐induced fear memory impairments in rodents. Antisense oligonucleotides (ASOs) targeting ATXN2 was a potential therapy for spinocerebellar ataxia, whose pathogenic mechanism associates with reduced BDNF expression. We tested the hypothesis that ASO7 targeting ATXN2 could affect BDNF levels in mouse basal forebrain and ameliorate sleep deprivation‐induced fear memory impairments. Methods Adult male C57BL/6 mice were used to evaluate the effects of ASO7 targeting ATXN2 microinjected into the bilateral basal forebrain (1 μg, 0.5 μL, each side) on spatial memory, fear memory and sleep deprivation‐induced fear memory impairments. Spatial memory and fear memory were detected by the Morris water maze and step‐down inhibitory avoidance test, respectively. Immunohistochemistry, RT‐PCR, and Western blot were used to evaluate the changes of levels of BDNF, ATXN2, and postsynaptic density 95 (PSD95) protein as well as ATXN2 mRNA. The morphological changes in neurons in the hippocampal CA1 region were detected by HE staining and Nissl staining. Results ASO7 targeting ATXN2 microinjected into the basal forebrain could suppress ATXN2 mRNA and protein expression for more than 1 month and enhance spatial memory but not fear memory in mice. BDNF mRNA and protein expression in basal forebrain and hippocampus was increased by ASO7. Moreover, PSD95 expression and synapse formation were increased in the hippocampus. Furthermore, ASO7 microinjected into the basal forebrain increased BDNF and PSD95 protein expression in the basal forebrain of sleep‐deprived mice and counteracted sleep deprivation‐induced fear memory impairments. Conclusion ASOs targeting ATXN2 may provide effective interventions for sleep deprivation‐induced cognitive impairments.

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Post-symptomatic Delivery of Brain-Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis

Cited by 17 publications

References 51 publications

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Spatial and temporal diversity of astrocyte phenotypes in Spinocerebellar ataxia type 1 mice

Antisense oligonucleotides targeting basal forebrain ATXN2 enhances spatial memory and ameliorates sleep deprivation‐induced fear memory impairment in mice

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