Biochemical Society transactions
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Biochem. Soc. Trans. · Aug 2012
ReviewDegradation of tau protein by autophagy and proteasomal pathways.
Tau aggregates are present in several neurodegenerative diseases and correlate with the severity of memory deficit in AD (Alzheimer's disease). However, the triggers of tau aggregation and tau-induced neurodegeneration are still elusive. ⋯ In the present paper, we focus on the regulation of the degradation of tau by the UPS and ALS and its relation to tau aggregation. We anticipate that stimulation of these two protein-degradation systems might be a potential therapeutic strategy for AD and other tauopathies.
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The NCLs (neuronal ceroid lipofuscinoses) (also known as Batten disease) are a group of at least ten fatal inherited storage disorders. Despite the identification of many of the disease-causing genes, very little is known about the underlying disease mechanisms. ⋯ These events are especially pronounced within the thalamocortical system, but it is clear that where and when they occur varies markedly between different forms of NCL. It is now becoming apparent that, despite having pathological endpoints that resemble one another, these are reached by a sequence of events that is specific to each subtype of NCL.
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Biochem. Soc. Trans. · Apr 2010
ReviewThe anti-allodynic alpha(2)delta ligand pregabalin inhibits the trafficking of the calcium channel alpha(2)delta-1 subunit to presynaptic terminals in vivo.
Neuropathic pain is caused by lesion or dysfunction of the peripheral sensory nervous system. Up-regulation of the voltage-gated Ca(2+) channel subunit alpha(2)delta-1 in DRG (dorsal root ganglion) neurons and the spinal cord correlates with the onset of neuropathic pain symptoms such as allodynia in several animal models of neuropathic pain. The clinically important anti-allodynic drugs gabapentin and pregabalin are alpha(2)delta-1 ligands, but how these drugs alleviate neuropathic pain is poorly understood. In the present paper, we review recent advances in our understanding of their molecular mechanisms.
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In neuronal circuits, memory storage depends on activity-dependent modifications in synaptic efficacy, such as LTD (long-term depression) and LTP (long-term potentiation), the two main forms of synaptic plasticity in the brain. In the nucleus striatum, LTD and LTP represent key cellular substrates for adaptive motor control and procedural memory. It has been suggested that their impairment could account for the onset and progression of motor symptoms of PD (Parkinson's disease), a neurodegenerative disorder characterized by the massive degeneration of dopaminergic neurons projecting to the striatum. ⋯ In those animals experiencing AIMs, synaptic plasticity is altered and is paralleled by modifications in the postsynaptic compartment. In particular, dysfunctions in trafficking and subunit composition of NMDARs [NMDA (N-methyl-D-aspartate) receptors] on striatal efferent neurons result from chronic non-physiological dopaminergic stimulation and contribute to the pathogenesis of dyskinesias. According to these pathophysiological concepts, therapeutic strategies targeting signalling proteins coupled to NMDARs within striatal spiny neurons could represent new pharmaceutical interventions for PD and L-dopa-induced dyskinesia.
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Biochem. Soc. Trans. · Aug 2009
ReviewAccelerated lung aging: a novel pathogenic mechanism of chronic obstructive pulmonary disease (COPD).
An enhanced or abnormal inflammatory response to the lungs to inhaled particles and gases, usually from cigarette smoke, is considered to be a general pathogenic mechanism in COPD (chronic obstructive pulmonary disease). Activation of leucocytes and the development of oxidant-antioxidant and protease-anti-protease imbalances are thought to be important aspects of this enhanced inflammatory response to cigarette smoke. The mechanisms involved in the perpetuation of the inflammatory response in the lungs in patients who develop COPD, even after smoking cessation, are not fully established and are key to our understanding of the pathogenic mechanisms in COPD and may be important for the development of new therapies. ⋯ There is also evidence that anti-aging molecules such as histone deacetylases and sirtuins are decreased in the lungs of COPD patients, compared with smokers without COPD, resulting in enhanced inflammation and further progression of COPD. The processes involved in accelerated aging may provide novel targets for therapy in COPD. The present article reviews the evidence for accelerated aging as a mechanism in the pathogenesis of COPD.