Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease

Ma, Qing; Yang, Jianmin; Li, Thomas; Milner, Teresa A.; Hempstead, Barbara L.

doi:10.1016/j.nbd.2015.08.008

Cited by 28 publications

(30 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We were unable to achieve specific labeling with the p75 antibody used in the Q111 and human post-mortem studies, and therefore a direct comparison with these studies is difficult (Brito et al, 2013, 2014). Interestingly, in the same Q175 model of HD used in this study, p75 levels were reported to be decreased at 12 months of age in both the heterozygous and homozygous mutants when compared to WT animals (Ma et al, 2015). p75 levels in the striatum, therefore, may vary depending on which HD mouse model is investigated.…”

Section: Discussionmentioning

confidence: 57%

“…Some expression of p75 in MSNs has been reported previously (Brito et al, 2014). A recent study, however, indicates that the majority of p75 in the striatum is expressed in immature oligodendrocytes, suggesting at least some p75 signaling is non-cell autonomous (Ma et al, 2015). Additionally, this enhanced survival signaling may be through p75 alone, through p75/TrkB complexes, or through p75 complexed with a different receptor.…”

Section: Discussionmentioning

confidence: 99%

“…To overcome this difficulty, Ma et al crossed the Q175 mouse line to a line expressing BDNF with an HA epitope tag. Using highly sensitive and specific HA antibodies, a decrease in BDNF protein levels in the striatum of Q175 mice at 6 months of age was observed (Ma et al, 2015). A decrease in BDNF levels and signaling in the striatum is proposed to contribute to the pathogenesis of HD (Zuccato and Cattaneo, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The p75 neurotrophin receptor augments survival signaling in the striatum of pre-symptomatic Q175 mice

et al. 2016

View full text Add to dashboard Cite

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a constellation of motor, cognitive, and psychiatric features. Striatal medium spiny neurons, one of the most affected populations, are dependent on brain-derived neurotrophic factor (BDNF) anterogradely transported from the cortex for proper function and survival. Recent studies suggest both receptors for BDNF, TrkB and p75 neurotrophin receptor (p75), are improperly regulated in the striata of HD patients and mouse models of HD. While BDNF–TrkB signaling almost exclusively promotes survival and metabolic function, p75 signaling is able to induce survival or apoptosis depending on the available ligand and associated co-receptor. We investigated the role of p75 in the Q175 knock-in mouse model of HD by examining the levels and activation of downstream signaling molecules, and subsequently examining Hdh+/Q175;p75−/− mice to determine if p75 represents a promising therapeutic target. In Hdh+/Q175;p75+/+ mice, we observed enhanced survival signaling as evidenced by an increase in phosphorylation and activation of Akt and the p65 subunit of NFκB in the striatum at 5 months of age and an increase in XIAP expression compared to Hdh+/+;p75+/+ mice; this increase was lost in Hdh+/Q175;p75−/− mice. Hdh+/Q175;p75−/− mice also showed a decrease in Bcl-XL expression by immunoblotting compared to Hdh+/Q175;p75+/+ and Hdh+/+;p75+/+ littermates. Consistent with diminished survival signaling, DARPP-32 expression decreased both by immunoblotting and by immunohistochemistry in Hdh+/Q175;p75−/− mice compared to Hdh+/+;p75+/+, Hdh+/Q175;p75+/+, and Hdh+/+;p75−/− littermates. Additionally, striatal volume declined to a greater extent in Hdh+/Q175;p75−/− when compared to Hdh+/Q175;p75+/+ littermates at 12 months, indicating a more aggressive onset of degeneration. These data suggest that p75 signaling plays an early role in augmenting pro-survival signaling in the striatum and that disruption of p75 signaling at a pre-symptomatic age may exacerbate pathologic changes in Hdh+/Q175 mice.

show abstract

Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The p75 neurotrophin receptor augments survival signaling in the striatum of pre-symptomatic Q175 mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…NTs bind to two types of receptors, denominated tropomyosin receptor kinases (Trks) and 75‐kDa pan‐NT receptor (p75 NTR ), that are classically thought to regulate pro‐survival and death signaling, respectively. A majority of studies report that NTs and/or Trks levels decrease while p75 NTR content increases in HD brain . In accordance, preclinical studies employing small molecule ligands modulating both types of receptors succeed in preventing HD‐related pathology, improving cognition and motor abilities .…”

Section: Introductionmentioning

confidence: 75%

Differential regulation of Kidins220 isoforms in Huntington's disease

et al. 2019

View full text Add to dashboard Cite

Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpainoveractivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.Kidins220-C33 reduction in HD Sebastián-Serrano et al Brain Pathology 30 (2020) 120-136

show abstract

“…In addition, BDNF can promote functional recovery of injured neurons following spinal cord injury [12][13][14] and stimulate the production of new neurons in the adult brain 15,16 . Loss of BDNF has also been suggested as a contributory factor to the progression of PD [17][18][19] , AD 20 and Huntington's disease (HD) [21][22][23] , as well as conditions such as depression 24,25 .…”

Section: Introductionmentioning

confidence: 99%

A single domain shark antibody targeting the transferrin receptor 1 delivers a TrkB agonist antibody across the blood brain barrier to provide full neuroprotection in a mouse model of Parkinson’s Disease

Clarke

L²,

Fletcher

et al. 2020

Preprint

View full text Add to dashboard Cite

Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells can be used to shuttle antibodies and other cargos across the blood brain barrier (BBB). We have fused one of these (TXB4) to differing regions of TrkB and TrkC neurotrophin receptor agonist antibodies (AAb) and determined the effect on agonist activity, brain accumulation and engagement with neurons in the mouse brain following systemic administration. The TXB4-TrkB and TXB4-TrkC fusion proteins retain agonist activity at their respective neurotrophin receptors and in contrast to their parental AAb they rapidly accumulate in the brain reaching nM levels following a single IV injection. Following SC administration, the most active TrkB fusion protein, TXB4-TrkB1, associates with and activates ERK1/2 signalling in TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc). When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD) TXB4-TrkB1, but not the parental TrkB AAb or a TXB4-TrkC1 fusion protein, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 TfR1 binding module allows a TrkB AAb to reach neuroprotective concentrations in the brain parenchyma following systemic administration.

show abstract

Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease

Cited by 28 publications

References 61 publications

The p75 neurotrophin receptor augments survival signaling in the striatum of pre-symptomatic Q175 mice

The p75 neurotrophin receptor augments survival signaling in the striatum of pre-symptomatic Q175 mice

Differential regulation of Kidins220 isoforms in Huntington's disease

A single domain shark antibody targeting the transferrin receptor 1 delivers a TrkB agonist antibody across the blood brain barrier to provide full neuroprotection in a mouse model of Parkinson’s Disease

Contact Info

Product

Resources

About