Nibbling away at synaptic development

Shen, Wei; Ganetzky, Barry

doi:10.4161/auto.6.1.10625

Cited by 17 publications

(11 citation statements)

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“…If these observations hold true, it also follows that therapies acting on cortical plasticity may help to ameliorate positive disease symptoms. In this context, the preliminary evidence we found implicating changes in autophagy may be important, insofar as autophagy is key to synaptic plasticity (Shen and Ganetzky, 2010) and is aberrant in neurodegenerative diseases, including Alzheimer's, Huntington's, Parkinson's, motor neuron, and prion diseases (Cherra et al, 2010). Recently, Horesh et al (2010) also reported BA22‐specific expression changes in the autophagy pathway in both Alzheimer's disease and schizophrenia.…”

Section: Discussionmentioning

confidence: 82%

“…When all the enriched processes in the BA22 region are considered, an overall theme emerges that may point to a widespread disruption in synaptic plasticity. This is seen directly in the processes of cell adhesion and synaptic contact, but also in cytoskeletal remodelling, an essential process underpinning plasticity, and in apoptosis and autophagy, two processes that are essential in the maintenance of synaptic structure (Bateup and Sabatini, 2010; Shen and Ganetzky, 2010). Changes in these pathways are robust to adjustment for age and are strengthened substantially when an exploratory disease threshold of P < 0.1 is used.…”

Section: Discussionmentioning

confidence: 99%

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Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia

Barnes

Huxley-Jones

Maycox

et al. 2011

J of Neuroscience Research

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The molecular basis of schizophrenia is poorly understood; however, different brain regions are believed to play distinct roles in disease symptomology. We have studied gene expression in the superior temporal cortex (Brodmann area 22; BA22), which may play a role in positive pathophysiology, and compared our results with data from the anterior prefrontal cortex (BA10), which shows evidence for a role in negative symptoms. Genome-wide mRNA expression was determined in the BA22 region in 23 schizophrenics and 19 controls and compared with a BA10 data set from the same subjects. After adjustments for confounding sources of variation, we carried out GeneGO pathway enrichment analysis in each region. Significant differences were seen in age-related transcriptional changes between the BA22 and the BA10 regions, 21.8% and 41.4% of disease-associated transcripts showing age association, respectively. After removing age associated changes from our data, we saw the highest enrichment in processes mediating cell adhesion, synaptic contact, cytoskeletal remodelling, and apoptosis in the BA22 region. For the BA10 region, we observed the strongest changes in reproductive signalling, tissue remodelling, and cell differentiation. Further exploratory analysis also identified potentially disease-relevant processes that were undetected in our more stringent primary analysis, including autophagy in the BA22 region and the amyloid process in the BA10 region. Collectively, our analysis suggests disruption of many common pathways and processes underpinning synaptic plasticity in both regions in schizophrenia, whereas individual regions emphasize changes in certain pathways that may help to highlight pathway-specific therapeutic opportunities to treat negative or positive symptoms of the disease.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia

Barnes

Huxley-Jones

Maycox

et al. 2011

J of Neuroscience Research

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“…In Drosophila larvae, autophagy promotes synaptic development at neuromuscular junctions (NMJ) [28]. Specifically, mutants of atg showed shrinkage of NMJ synapses and reduction of bouton numbers.…”

Section: Introductionmentioning

confidence: 99%

Neuronal Autophagy and Neurodevelopmental Disorders

2013

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Neurodevelopmental disorders include a wide range of diseases such as autism spectrum disorders and mental retardation. Mutations in several genes that regulate neural development and synapse function have been identified in neurodevelopmental disorders. Interestingly, some affected genes and pathways in these diseases are associated with the autophagy pathway. Autophagy is a complex, bulky degradative process that involves the sequestration of cellular proteins, RNA, lipids, and cellular organelles into lysosomes. Despite recent progress in elucidating the genetics and molecular pathogenesis of these disorders, little is known about the pathogenic mechanisms and autophagy-related pathways involved in common neurodevelopmental disorders. Therefore, in this review, we focus on the current understanding of neuronal autophagy as well as recent findings on genetics and the roles of autophagy pathway in common neurodevelopmental disorders.

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“…Vesicle expansion and completion are a multistep process controlled by two ubiquitin-like proteins, Atg7 and Atg12. Posttranslational modification of Atg8 results in the recruitment to the preautophagosomal structure membrane affects spine remodelling exclusively via protein synthesis or other TOR-controlled pathways is still under debate as genetic evidences have shown that altered autophagy can promote synaptic growth [14]. In summary, by integrating signaling information from growth factors, nutrients, intracellular energy status and environmental cues, TOR controls cellular metabolism, promotes longevity and has a broad positive impact on ageing and on neuronal function [15].…”

Section: Introductionmentioning

confidence: 99%

Ageing, Neuronal Connectivity and Brain Disorders: An Unsolved Ripple Effect

et al. 2011

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Cognitive decline associated with ageing and age-related disorders emerges as one of the greatest health challenges in the next decades. To date, the molecular mechanisms underlying the onset of neuronal physiological changes in the central nervous system remain unclear. Functional MRI and PET studies have indicated the decline in working memory performance in older adults. Similarly, age-related disorders, such as Alzheimer's disease, are associated with changes in the prefontral cortex and related neural circuitry, which underlines the decline of integrative function between different brain regions. This is mainly attributed to the loss of synaptic connectivity, which is a feature commonly observed in neurodegenerative disorders. In humans, the morphological and functional changes in neurons, such as reduction of spine numbers and synaptic dysfunction, precede the first signs of cognitive decline and likely contribute to pathology progression. Thus, a new scenario emerges in which apparently unrelated diseases present common features, such as the remodelling of neuronal circuitries promoted by ageing. For many years, ageing was considered a process of slow deterioration triggered by accidental environmental factors. Conversely, it is now evident that ageing is a biological process tightly controlled by evolutionary highly conserved signalling pathways. Importantly, genetic mutations that enhance longevity significantly delay the loss of synaptic connectivity and, therefore, the onset of age-related brain disorders. Accordingly, tweaking ageing might be an attractive approach to prevent cognitive decline caused by age-related synaptic dysfunction.

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Nibbling away at synaptic development

Cited by 17 publications

References 0 publications

Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia

Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia

Neuronal Autophagy and Neurodevelopmental Disorders

Ageing, Neuronal Connectivity and Brain Disorders: An Unsolved Ripple Effect

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