P.2.b.017 Biologic epistasis between SERT and BDNF: complex genetic mechanisms of depression

Pezawas, Lukas; Goldman, A.L.; Verchinski, Beth A.; Mattay, V.A.; Callicott, J.H.; Kolachana, Bhaskar; Straub, Richard E.; Egan, Michael; Meyer‐Lindenberg, Andreas; Weinberger, D.R.

doi:10.1016/s0924-977x(06)70331-5

Cited by 5 publications

(10 citation statements)

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“…The V66M mutation leads to the reduction in activitydependent secretion and impairs the intracellular trafficking of BDNF without affecting the constitutive release of BDNF (26,61). This mutation in human also causes the reduction in hippocampal volume (28) and affects hippocampal processing of episodic learning and memory (27). The phenomenon suggests that the impairment of activity-dependent secretion of BDNF is responsible for dysfunction in hippocampal plasticity and for a number of human psychological disorders (62).…”

Section: Mutant Htt Affects the Association Of Hap1 With Pro-bdnf-mentioning

confidence: 99%

“…A single nucleotide polymorphism in the BDNF gene (BDNFmet) at codon 66 in the prodomain results in the reduction of BDNF transport and activity-dependent secretion (26). The mutation was associated with reduction of hippocampal volume, impairment of episodic learning (27,28), and a number of neurological disorders (29 -31).The polyglutamine (polyQ) expansion in Huntingtin (Htt) and knocking down of Htt-associated protein-1 (HAP1) and p150Glued can reduce BDNF transport and lead to the degeneration of striatal neurons (26,32). Htt is a scaffold protein predominantly found in the cytoplasm where it associates with various vesicular structures and molecular motors to form a cargo complex and may play a role in intracellular trafficking (32,33).…”

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Huntingtin-associated Protein-1 Interacts with Pro-brain-derived Neurotrophic Factor and Mediates Its Transport and Release

Fan

et al. 2010

Journal of Biological Chemistry

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Brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain development and synaptic plasticity. It is synthesized as a precursor (pro-BDNF), sorted into the secretory pathway, transported along dendrites and axons, and released in an activity-dependent manner. Mutant Huntingtin with expanded polyglutamine (polyQ) and the V66M polymorphism of BDNF reduce the dendritic distribution and axonal transport of BDNF. However, the mechanism underlying this defective transport remains unclear. Here, we report that Huntingtin-associated protein-1 (HAP1) interacts with the prodomain of BDNF and that the interaction was reduced in the presence of polyQ-expanded Huntingtin and BDNF V66M. Consistently, there was reduced coimmunoprecipitation of pro-BDNF with HAP1 in the brain homogenate of Huntington disease. Pro-BDNF distribution in the neuronal processes and its accumulation in the proximal and distal segments of crushed sciatic nerve and the activity-dependent release of pro-BDNF were abolished in HAP1 ؊/؊ mice. These results suggest that HAP1 may participate in axonal transport and activity-dependent release of pro-BDNF by interacting with the BDNF prodomain. Accordingly, the decreased interaction between HAP1 and pro-BDNF in Huntington disease may reduce the release and transport of BDNF.Neurotrophins play important roles in the proliferation, differentiation, and survival of neurons during development and in the maintenance of normal functions of the mature nervous system by activating their respective tyrosine kinase receptors TrkA, TrkB, and TrkC and the common receptor p75NTR (1-6). Neurotrophins are synthesized as precursors (proneurotrophins), which are either cleaved intracellularly by furin (2, 7, 8) and released as mature forms (9), or cleaved extracellularly by several proteases, including prohormone convertases, tissue-activated plasminogen/plasmin, 10,11). Recently, it has been shown that unprocessed, the nerve growth factor precursor and the brain-derived neurotrophic factor precursor (pro-BDNF) 3 bind both Sortilin and p75NTR with a high affinity and preferentially activate p75NTR, leading to apoptosis (12-15).Although the retrograde neurotrophic hypothesis is well recognized, accumulating evidence indicates that neurotrophins such as BDNF and neurotrophin-3 are also trafficked anterogradely within dendrites and axons, released in an activity-dependent manner, and uptaken by second-or third-order target neurons (16 -19). The anterogradely transported and released BDNF regulates neuronal survival, differentiation, dendritic morphology, and synaptic plasticity (17, 20 -22). Both Sortilin and carboxypeptidase E play important roles in post-translational Golgi sorting of BDNF to the regulated secretory pathway and activity-dependent release by interacting with the prodomain (23) and the mature domain, respectively (24). Recently, we showed that pro-BDNF, like mature BDNF, is also transported anterogradely and retrogradely within axons of sensory neurons (25). However, how pro-BDNF and mature BDNF are...

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Section: Mutant Htt Affects the Association Of Hap1 With Pro-bdnf-mentioning

confidence: 99%

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Huntingtin-associated Protein-1 Interacts with Pro-brain-derived Neurotrophic Factor and Mediates Its Transport and Release

Fan

et al. 2010

Journal of Biological Chemistry

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“…For example, methionine substitution at codon 66 reduces BDNF transport and activity-dependent secretion (3). This polymor-phism also causes reduction of hippocampal volume, impairment of episodic learning (45,46), and a number of neurological disorders (47)(48)(49). However, the mechanism underlying the defect in BDNF trafficking remains unknown.…”

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Precursor of Brain-derived Neurotrophic Factor (proBDNF) Forms a Complex with Huntingtin-associated Protein-1 (HAP1) and Sortilin That Modulates proBDNF Trafficking, Degradation, and Processing

Yang

Lim

et al. 2011

Journal of Biological Chemistry

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proBDNF, a precursor of brain-derived neurotrophic factor (BDNF), is anterogradely transported and released from nerve terminals, but the mechanism underlying this process remains unclear. In this study, we report that proBDNF forms a complex with Huntingtin associated protein-1 (HAP1) and sortilin, which plays an important role in proBDNF intracellular trafficking and stabilization. The interaction of proBDNF with both HAP1A and sortilin in co-transfected HEK293 cells is confirmed by both fluorescence resonance energy transfer and coimmunoprecipitation. The frequent co-localization (>90%) of endogenous HAP1, sortilin, and proBDNF is also found in cultured cortical neurons. Mapping studies using GST pulldown and competition assays has defined the interacting region of HAP1 with proBDNF within amino acids 371-445 and the binding sequences of proBDNF to HAP1 between amino acids 65 and 90. Fluorescence recovery after photobleaching confirms the defective movement of proBDNF-containing vesicles in neurites of HAP1 ؊/؊ neurons, which can be partially restored by reintroducing HAP1 cDNA into the neurons. However, the effect is significantly increased by simultaneously reintroducing both HAP1 and sortilin. proBDNF and HAP1 are highly co-localized with organelle markers for the Golgi network, microtubules, molecular motor, or endosomes in normal neurons, but this co-localization is reduced in HAP1 ؊/؊ neurons.Co-immunoprecipitation and Western blot showed that sortilin stabilizes the proBDNF⅐HAP1 complex in co-transfected HEK293 cells, helping to prevent proBDNF degradation. Furthermore, the complex facilitates furin cleavage to release mature BDNF.

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“…Also, this group showed a reduced hippocampal engagement during encoding and retrieval as indicated by fMRI. In addition, val/val carriers have been reported to have smaller hippocampal volume than val/met heterozygotes (Bueller et al, 2006;Pezawas et al, 2004). Some studies have reported that the met allele is a risk factor for cognitive impairment in aging (Miyajima et al, 2008;Nagel et al, 2008;Raz, Rodrigue, Kennedy, & Land, 2009), whereas other work report of opposite findings where the met allele may protect against cognitive decline (Erickson et al, 2008;Harris et al, 2005).…”

Section: Bdnf and Cognitionmentioning

confidence: 99%

Olfactory Function: The Influence of Demographic, Cognitive, and Genetic factors

Hedner¹

2013

PsycEXTRA Dataset

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Olfactory function is affected by demographic, cognitive, and genetic factors. In the present thesis, three empirical studies investigated individual differences in olfactory ability. Study I explored demographic and cognitive correlates in common olfactory tasks; odor detection, odor discrimination, and odor identification. The results indicated that old age influenced performance negatively in all tasks, and that semantic memory proficiency and executive functioning were related to odor discrimination and odor identification performance. No cognitive influence was observed for measurements of olfactory threshold. Using population-based data, Study II investigated a potential influence of the ApoE gene on olfactory identification after controlling for health status, semantic memory, and preclinical and clinical dementia. The main finding was that the ApoE-ɛ4 allele interacted with age, such that older ɛ4-carriers had an impaired odor identification performance relative to older non-carriers. Importantly, the negative ApoE-ɛ4 effect on olfactory proficiency was independent of clinical dementia conversion within five years. Study III investigated the effects of the BDNF val66met polymorphism on olfactory change over a five-year interval, in a communitydwelling sample of young and old age cohorts. The results showed that agerelated decline in olfactory identification was influenced by the BDNF val66met. In middle-aged subjects, no effect of BDNF val66met was observed although older val homozygote carriers showed a selectively larger olfactory decline than the older met carriers. Overall, results suggest that the relative influence of demographic and cognitive factors vary across different olfactory tasks and that two genes (ApoE and BDNF) impact age-related deficits in odor identification. Potential theoretical and practical implications of the findings are discussed as well as potential limitations of association studies in genomics research.

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P.2.b.017 Biologic epistasis between SERT and BDNF: complex genetic mechanisms of depression

Cited by 5 publications

References 0 publications

Huntingtin-associated Protein-1 Interacts with Pro-brain-derived Neurotrophic Factor and Mediates Its Transport and Release

Huntingtin-associated Protein-1 Interacts with Pro-brain-derived Neurotrophic Factor and Mediates Its Transport and Release

Precursor of Brain-derived Neurotrophic Factor (proBDNF) Forms a Complex with Huntingtin-associated Protein-1 (HAP1) and Sortilin That Modulates proBDNF Trafficking, Degradation, and Processing

Olfactory Function: The Influence of Demographic, Cognitive, and Genetic factors

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