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Failure of normal brain development leads to mental retardation or autism in about 3% of children. Many genes integral to pathways by which synaptic modification and the remodelling of neuronal networks mediate cognitive and social development have been identified, usually through loss of function. Evidence is accumulating, however, that either loss or gain of molecular functions can be deleterious to the nervous system. Copy-number variation, regulation of gene expression by non-coding RNAs and epigenetic changes are all mechanisms by which altered gene dosage can cause the failure of neuronal homeostasis. 相似文献
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Bowman AB Lam YC Jafar-Nejad P Chen HK Richman R Samaco RC Fryer JD Kahle JJ Orr HT Zoghbi HY 《Nature genetics》2007,39(3):373-379
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, we generated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathology. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis. 相似文献
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Flagel SB Clark JJ Robinson TE Mayo L Czuj A Willuhn I Akers CA Clinton SM Phillips PE Akil H 《Nature》2011,469(7328):53-57
Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards can acquire motivational properties, becoming attractive and desirable incentive stimuli. However, whether a cue acts solely as a predictor of reward, or also serves as an incentive stimulus, differs between individuals. Thus, individuals vary in the degree to which cues bias choice and potentially promote maladaptive behaviour. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus-reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of stimulus-reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus-reward learning that confers increased susceptibility to disorders of impulse control. 相似文献