Serotonergic dysfunction in Parkinson's disease and its relevance to disability.
Ontology highlight
ABSTRACT:
SUBMITTER: Politis M
PROVIDER: S-EPMC3201695 | biostudies-other | 2011
REPOSITORIES: biostudies-other
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Project description:Parkinson's disease, neuropathologically defined by the aggregation of α-synuclein, is characterized by neuropsychiatric symptoms such as depression and anxiety preceding the onset of motor symptoms. A loss of serotonergic neurons or their projections into the hippocampus and alterations in serotonin release may be linked to these symptoms. Here, we investigate the effect of human A53T α-synuclein on serotonergic neurons using 12-months-old transgenic mice. We detected human α-synuclein in the perikarya of brainstem median and dorsal raphe neurons as well as in serotonergic fibers in the hippocampus. Despite intracellular α-synuclein accumulation there was no loss of serotonergic neurons in dorsal and median raphe nuclei of A53T α-synuclein mice. However, serotonin levels were significantly reduced in the brainstem. In addition, serotonergic fiber density in the dorsal dentate gyrus was significantly less dense in transgenic mice. Interestingly, we detected a significantly compromised increase in doublecortin+ neuroblasts after chronic treatment with fluoxetine at the site of reduced serotonergic innervation, the infrapyramidal blade of the dorsal dentate gyrus in A53T α-synuclein mice. This suggests that α-synuclein affects serotonergic projections in a spatially distinct pattern within the hippocampus thereby influencing the response to antidepressant treatment.
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Project description:Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share similar pathophysiological mechanisms. From a neurochemical point of view, the serotonin (5-hydroxytryptamine; 5-HT) dysfunction in both movement disorders-related to probable lesioning of the raphe nuclei-is profound, and, therefore, may be partially responsible for motor as well as non-motor disturbances. More specifically, in ALS, it has been hypothesized that serotonergic denervation leads to loss of its inhibitory control on glutamate release, resulting into glutamate-induced neurotoxicity in lower and/or upper motor neurons, combined with a detrimental decrease of its facilitatory effects on glutamatergic motor neuron excitation. Both events then may eventually give rise to the well-known clinical motor phenotype. Similarly, disruption of the organized serotonergic control on complex mesencephalic dopaminergic connections between basal ganglia (BG) nuclei and across the BG-cortico-thalamic circuits, has shown to be closely involved in the onset of parkinsonian symptoms. Levodopa (L-DOPA) therapy in PD largely seems to confirm the influential role of 5-HT, since serotonergic rather than dopaminergic projections release L-DOPA-derived dopamine, particularly in extrastriatal regions, emphasizing the strongly interwoven interactions between both monoamine systems. Apart from its orchestrating function, the 5-HT system also exerts neuroprotective and anti-inflammatory effects. In line with this observation, emerging therapies have recently focused on boosting the serotonergic system in ALS and PD, which may provide novel rationale for treating these devastating conditions both on the disease-modifying, as well as symptomatic level.
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Project description:Sleep disturbances are common non-motor symptoms in Parkinson's disease (PD). Experimental studies suggest involvement of the serotonergic system in the regulation of sleep and arousal. Using [11C]DASB positron emission tomography, a marker of serotonin transporter availability, we investigated whether sleep dysfunction is associated with serotonergic dysfunction in PD.We studied 14 PD patients with sleep dysfunction, 14 PD without sleep dysfunction, and 12 healthy controls. Groups were matched for age, disease duration, severity of motor symptoms, daily intake of levodopa equivalent units, body-mass-index, depression and fatigue. [11C]DASB non-displaceable binding potential (BPND) was calculated for regions with a role in the regulation of sleep and arousal.[11C]DASB BPND was reduced by 32-49% in PD patients with sleep dysfunction, and 14-25% in PD without sleep dysfunction, compared to healthy controls. PD patients with sleep dysfunction had lower [11C]DASB BPND in caudate (P?<?0.01), putamen (P?<?0.001), ventral striatum (P?<?0.001), thalamus (P?<?0.05), hypothalamus (P?<?0.001) and raphe nuclei (P?<?0.01), compared to PD without sleep dysfunction. Higher severity of sleep symptoms (assessed with Parkinson Disease Sleep Scale) correlated with lower [11C]DASB binding in caudate (r?=?0.77; P?<?0.001), putamen (r?=?0.84; P?<?0.001), ventral striatum (r?=?0.86; P?<?0.001), thalamus (r?=?0.79; P?<?0.001), hypothalamus (r?=?0.90; P?<?0.001) and raphe nuclei (r?=?0.83; P?<?0.001).Our findings demonstrate that sleep dysfunction in PD is associated with reduced serotonergic function in the midbrain raphe, basal ganglia and hypothalamus. Strategies to increase serotonin levels in the brain could be a promising approach to treat sleep dysfunction in PD, and may also have relevance in other neurodegenerative disorders.
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Project description:Recognition of the importance of nonmotor dysfunction as a component of Parkinson's disease has exploded over the past three decades. Autonomic dysfunction is a frequent and particularly important nonmotor feature because of the broad clinical spectrum it covers. Cardiovascular, gastrointestinal, urinary, sexual, and thermoregulatory abnormalities all can appear in the setting of Parkinson's disease. Cardiovascular dysfunction is characterized most prominently by orthostatic hypotension. Gastrointestinal dysfunction can involve virtually all levels of the gastrointestinal tract. Urinary dysfunction can entail either too frequent voiding or difficulty voiding. Sexual dysfunction is frequent and frustrating for both patient and partner. Alterations in sweating and body temperature are not widely recognized but often are present. Autonomic dysfunction can significantly and deleteriously impact quality of life for individuals with Parkinson's disease. Because effective treatment for many aspects of autonomic dysfunction is available, it is vitally important that assessment of autonomic dysfunction be a regular component of the neurologic history and exam and that appropriate treatment be initiated and maintained.
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Project description:Despite decades of research, current therapeutic interventions for Parkinson's disease (PD) are insufficient as they fail to modify disease progression by ameliorating the underlying pathology. Cellular proteostasis (protein homeostasis) is an essential factor in maintaining a persistent environment for neuronal activity. Proteostasis is ensured by mechanisms including regulation of protein translation, chaperone-assisted protein folding and protein degradation pathways. It is generally accepted that deficits in proteostasis are linked to various neurodegenerative diseases including PD. While the proteasome fails to degrade large protein aggregates, particularly alpha-synuclein (α-SYN) in PD, drug-induced activation of autophagy can efficiently remove aggregates and prevent degeneration of dopaminergic (DA) neurons. Therefore, maintenance of these mechanisms is essential to preserve all cellular functions relying on a correctly folded proteome. The correlations between endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway are well-established. However, while mild insults increase the activity of chaperones, prolonged cell stress, or insufficient adaptive response causes cell death. Modulating the activity of molecular chaperones, such as protein disulfide isomerase which assists refolding and contributes to the removal of unfolded proteins, and their associated pathways may offer a new approach for disease-modifying treatment. Here, we summarize some of the key concepts and emerging ideas on the relation of protein aggregation and imbalanced proteostasis with an emphasis on PD as our area of main expertise. Furthermore, we discuss recent insights into the strategies for reducing the toxic effects of protein unfolding in PD by targeting the ER UPR pathway.
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