alpha-synuclein and Depressive-Disorder

Parkinson's disease is one of the most frequent progressive degenerative disorders with unknown origin of the nervous system. The commutation of the disease on Guam led to the discovery of a neurotoxin which was also found in other continents. This neurotoxin was identified in the common cyanobacteria (blue-green algae). Early clinical observations suggested some loose correlations with gastric and duodenal ulcer and Parkinson's disease, while recent studies revealed a toxin, almost identical to that found in cyanobacteria in one strain of Helicobacter pylori, which proved to cause Parkinson like symptoms in animals. Therefore, it cannot be ruled out that there is a slowly progressive poisoning in Parkinson's disease. The disease specific alpha-sinuclein inclusions can be found in nerve cells of the intestinal mucosa far before the appearance of clinical symptoms indicating that the disease may start in the intestines. These results are strengthened by the results of Borody's fecal transplants, after which in Parkinson patients showed a symptomatic improvement. Based on these observations the Parkinson puzzle is getting complete. Although these observations are not evidence based, they may indicate a new way for basic clinical research, as well as a new way of thinking for clinicians. These new observations in psycho-neuro-immunology strengthen the fact that immunological factors may also play a critical factor facilitating local cell necrosis which may be influenced easily.

Topics: alpha-Synuclein; Amino Acids, Diamino; Amyotrophic Lateral Sclerosis; Animals; Chiroptera; Cyanobacteria Toxins; Dementia; Depression; Depressive Disorder; Duodenal Ulcer; Encephalitis; Excitatory Amino Acid Agonists; Feces; Helicobacter Infections; Helicobacter pylori; Humans; Intestines; Lewy Bodies; Oxidative Stress; Parkinson Disease; Sleep Initiation and Maintenance Disorders; Stomach Ulcer

Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are increasingly recognized as alpha-synucleinopathies, i.e. neurodegenerative disorders that share a common subcellular pathology characterized by alpha-synuclein abnormal aggregation. In the present review we focus on depression in alpha-synucleinopathies, discussing epidemiological, pathophysiological and treatment aspects of this frequently disabling clinical feature which may occur in PD, DLB and MSA alike.

Topics: alpha-Synuclein; Animals; Antidepressive Agents; Brain; Depressive Disorder; Diagnosis, Differential; Humans; Lewy Body Disease; Multiple System Atrophy; Nerve Tissue Proteins; Parkinson Disease; Prevalence; Synucleins

The α-synuclein gene (SNCA) multiplication causes autosomal dominant Parkinson's disease (PD). Particularly triplication, but also duplication, of the SNCA is associated with early-onset rapidly progressing parkinsonism with increased risk of cognitive impairment. There is no report about the effect and safety of Deep Brain Stimulation (DBS) in carriers of this mutation and, in general, data in patients with genetic parkinsonism are scarce. We report a one-year prospective follow-up of subthalamic nucleus (STN) DBS in a 46-year old female carrier of SNCA duplication who developed PD at the age of 41 years, and rapidly showed disabling motor fluctuations and dyskinesias refractory to pharmacological strategies. One year after surgery there was a clinically relevant improvement in motor features with a reduction of 64% in UPDRS III in "off medication" and a complete abolition of peak dose dyskinesias. Patient did not report procedure-related adverse events following STN-DBS except for stimulation-induced right foot dystonia relieved by modulating stimulation parameters. Postoperative cognitive testing showed a decline in executive functions, mostly verbal fluency and attention shifting, compared with presurgical assessment. STN-DBS is safe and effective in patients with SNCA duplication showing a clinical pattern similar to idiopathic PD. Our case suggests that clinical phenotype rather genotype is the main predictor for DBS outcome.

Topics: Adult; alpha-Synuclein; Antiparkinson Agents; Deep Brain Stimulation; Depressive Disorder; Dystonia; Executive Function; Female; Follow-Up Studies; Functional Laterality; Gene Duplication; Humans; Levodopa; Neuropsychological Tests; Neurosurgical Procedures; Parkinson Disease; Subthalamic Nucleus; Treatment Outcome

Susceptibility to stress plays a crucial role in the development of psychiatric disorders such as unipolar depression and post-traumatic stress disorder. In the present study the chronic mild stress rat model of depression was used to reveal stress-susceptible and stress-resilient rats. Large-scale proteomics was used to map hippocampal protein alterations in different stress states. Membrane proteins were successfully captured by two-phase separation and peptide based proteomics. Using iTRAQ labeling coupled with mass spectrometry, more than 2000 proteins were quantified and 73 proteins were found to be differentially expressed. Stress susceptibility was associated with increased expression of a sodium-channel protein (SCN9A) currently investigated as a potential antidepressant target. Differential protein profiling also indicated stress susceptibility to be associated with deficits in synaptic vesicle release involving SNCA, SYN-1, and AP-3. Our results indicate that increased oxidative phosphorylation (COX5A, NDUFB7, NDUFS8, COX5B, and UQCRB) within the hippocampal CA regions is part of a stress-protection mechanism.

Topics: Adaptation, Biological; alpha-Synuclein; Animals; Biomarkers; Depressive Disorder; Disease Models, Animal; DNA-Binding Proteins; Gene Expression; Gene Expression Profiling; Hippocampus; Male; Mass Spectrometry; Oxidative Phosphorylation; Photic Stimulation; Proteomics; Rats; Rats, Wistar; Stress, Physiological; Sucrose; Synapsins; Synaptic Vesicles; Transcription Factors

The mechanisms underlying depression remain elusive. We previously determined that alpha-synuclein (alpha-Syn) modulates the activity and trafficking of the norepinephrine transporter (NET) in a manner that is dependent on its interactions with microtubules (MTs). Here we sought to determine if alpha-Syn, or the other synuclein family members, beta-synuclein (beta-Syn) and gamma-synuclein (gamma-Syn), modulate NET activity in an animal model of depression, the Wistar-Kyoto (WKY) rat. The NET-selective antidepressant desipramine (DMI) was chronically administered for 14 days to WKY rats and the strain from which it was outbred that does not show depressive-like behavior, the Wistar rat. This drug regimen induced significant behavioral improvements in the WKY, but not the Wistar rat, in the forced swim test. In WKY rats there was an overexpression of gamma-Syn which was reduced following DMI treatment. In parallel, DMI caused an increase in both alpha-Syn and NET in the frontal cortex. Frontal cortex synaptosomes from WKY rats were not sensitive to nocodazole, a compound that promotes MT destabilization. However, in WKYs treated with DMI, nocodazole induced an increase in [(3)H]-NE uptake. This trend was reversed in Wistars. Underlying these DMI-induced changes were alterations in the protein interactions between the synucleins and NET with the tubulins. These results are the first to implicate alpha-Syn or gamma-Syn in the pathophysiology of depression and suggest that targeting synucleins may provide a new therapeutic option for depression.

Topics: alpha-Synuclein; Animals; Antidepressive Agents, Tricyclic; Behavior, Animal; beta-Synuclein; Cytoskeleton; Depressive Disorder; Desipramine; Disease Models, Animal; Frontal Lobe; gamma-Synuclein; Male; Microtubules; Nocodazole; Norepinephrine Plasma Membrane Transport Proteins; Rats; Rats, Inbred WKY; Rats, Wistar; Synaptosomes; Trillium

Topics: Aged; alpha-Synuclein; Atrophy; Brain; Cognition Disorders; Depressive Disorder; Diagnosis, Differential; Disease Progression; Electroencephalography; Fatal Outcome; Gait Disorders, Neurologic; Genetic Markers; Genetic Predisposition to Disease; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Memory Disorders; Psychotic Disorders; REM Sleep Behavior Disorder; Sleep Apnea Syndromes; Urination Disorders