Activation of TrkB-Akt signaling rescues deficits in a mouse model of SCA6

Cook, Anna A.; Jayabal, Sriram; Sheng, Jacky; Fields, Eviatar; Leung, Tsz Chui Sophia; Quilez, Sabrina; McNicholas, Eileen; Lau, Lois; Huang, Shixia; Watt, Alanna J.

doi:10.1126/sciadv.abh3260

Cited by 18 publications

(52 citation statements)

References 82 publications

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“…The level of BDNF accumulation within the early endosomes was also restored (Fig. 7d), suggesting that in addition to self-amplifying upregulation of TrkB (Cook et al, 2022)…”

Section: 8-dhf Rescues Deficits In Early Endosomesmentioning

confidence: 84%

“…Thus, early endosomes are enlarged and accumulate BDNF and TrkB in SCA6, despite decreased levels of both proteins in the SCA6 cerebellum as a whole. This cargo mis-trafficking could lead to a decrease in the amount of free BDNF available to signal, as well as the amount of TrkB recycled to the cell surface, thereby contributing to previously described BDNF-TrkB signaling deficits in SCA6 (Cook et al, 2022). (f) Relative staining level of BDNF within early endosome compartment is higher in the Purkinje cells of SCA6 mice compared to WT (P < 0.001; N = 6 WT mice, 173 cells; 5 SCA6 mice, 171 cells).…”

Section: Early Endosomes Are Enlarged and Accumulate Bdnf And Trkb In...mentioning

confidence: 98%

“…However, it has been unknown whether endo-lysosomal pathway dysregulation is implicated in the natural disease progression of SCA6, or whether other endosomal compartments may be involved. We have recently found that deficits in the BDNF-TrkB-Akt signaling pathway contribute to SCA6 pathophysiology (Cook et al, 2022), with both BDNF and TrkB expression reduced in the cerebellar vermis. However, the underlying causes of the reduced levels of BDNF and TrkB remained unknown.…”

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confidence: 99%

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Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6

Cook,

Leung,

Rice

et al. 2023

Preprint

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Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-DHF, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6, and a promising therapeutic target.

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“…The level of BDNF accumulation within the early endosomes was also restored (Fig. 7d), suggesting that in addition to self-amplifying upregulation of TrkB (Cook et al, 2022)…”

Section: 8-dhf Rescues Deficits In Early Endosomesmentioning

confidence: 84%

Section: Early Endosomes Are Enlarged and Accumulate Bdnf And Trkb In...mentioning

confidence: 98%

mentioning

confidence: 99%

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Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6

Cook,

Leung,

Rice

et al. 2023

Preprint

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“…Postmortem analysis of patients' brains affected by SCA6, for example, has shown reduced BDNF. In a mouse model of SCA6, allowing more precise analysis, BDNF and TrkB were downregulated at the age-at-onset, and early activation of TrkB-AKT signalling improved symptoms 57 . These data support not only the importance of early disruption of BDNF-TRkB signalling in PolyQ diseases but also our novel findings whereby early manipulation of TrkB signalling regulated pathways (here the GSH metabolism) is fundamental to halt the degenerative process in iSPNs lacking BDNF-TrkB signalling relevant to HD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Impaired striatal glutathione metabolism induces dopamine increase and motor dysfunction.

Malik

Guo

Asif-Malik

et al. 2023

Preprint

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Identification of initial triggering events in neurodegenerative disorders is critical to the development of preventive therapies. In Huntington’s disease (HD), hyperdopaminergia triggered by dysfunction of inhibitory indirect pathway spiny projection neurons (iSPNs) is believed to induce hyperkinesia, an early-stage HD symptom. Loss of TrkB signalling in iSPNs results in spontaneous motor dysfunction consistent with early HD hyperkinesia. We now show that this is preceded by striatal hyperdopaminergia at the pre-symptomatic stage induced by an increase in midbrain dopaminergic neurons. iSPNs transcriptome analysis revealed de-regulation of metabolic pathways in the absence of TrkB signalling, including up-regulation of Gsto2, encoding the glutathione S-transferase omega-2 (GSTO2). Selective in vivo knockdown of Gsto2 in iSPNs was sufficient to prevent dopaminergic dysfunction and block the onset of HD-like motor symptoms, identifying a functional link between iSPN dysfunction and striatal hyperdopaminergia and a putative disease-modifying enzyme that may be targeted in early stages of HD.

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“…We performed immunohistochemistry to demonstrate that CN neurons do not express ChR2 by perfusing mice and labeling for NeuN and anti-green fluorescent protein (GFP). For both immunohistochemistry and viral labeling experiments, we prepared slices from animals by deeply anesthetizing mice with 2,2,2-tribromoethanol (avertin, 0.02 mL/10g) via intraperitoneal injection, followed by intracardiac perfusion 43 . We performed an initial flush using PBS and 5.6 μg/ml heparin salt, followed by perfusion with 40 ml of 4% PFA in phosphate buffer (PB, pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

Structured connectivity in the output of the cerebellar cortex

Gruver

Fields

et al. 2023

Preprint

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Circuits in the brain are built from connections between neurons, where the spatial organization and functional properties of these connections determines circuit function. In the cerebellum, Purkinje cells transmit information to neurons in the cerebellar nuclei, but how Purkinje cell - nuclear neuron connections are organized remains unclear. Here, we explored the connections between Purkinje cells and cerebellar nuclear neurons using whole-cell electrophysiology and optogenetics to produce spatial connectivity maps of cerebellar cortical output. We observed non-random connectivity between Purkinje cells and their target neurons, with inputs to cerebellar nuclear neurons clustering along cerebellar transverse zones. While many nuclear neurons received inputs from a single zone, a number of different connectivity motifs were observed. Neurons receiving inputs from all four zones were more common than predicted by a random model and showed topographic organization in the nucleus. Finally, we observed that small Purkinje cell inputs were sufficient to pause the output of nuclear neurons, suggesting that widespread Purkinje cell synchrony may not be necessary to influence cerebellar output. These findings reveal cerebellar nuclear neurons as an important locus of multimodal cerebellar integration.

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Activation of TrkB-Akt signaling rescues deficits in a mouse model of SCA6

Cited by 18 publications

References 82 publications

Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6

Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6

Impaired striatal glutathione metabolism induces dopamine increase and motor dysfunction.

Structured connectivity in the output of the cerebellar cortex

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