Roles for Mitochondrial Complex I subunits in regulating synaptic transmission and growth

To identify conserved components of synapse function that are also associated with human diseases, we conducted a genetic screen. We used the Drosophila melanogaster neuromuscular junction (NMJ) as a model. We employed RNA interference (RNAi) on selected targets and assayed synapse function by electrophysiology. We focused our screen on genetic factors known to be conserved from human neurological or muscle functions (321 total RNAi lines screened). Knockdown of a particular Mitochondrial Complex I (MCI) subunit gene (ND-20L) lowered levels of NMJ neurotransmission. Due to the severity of the phenotype, we studied MCI function further. Knockdown of core MCI subunits concurrently in neurons and muscle led to impaired neurotransmission. Further, pharmacology targeting MCI phenocopied the impaired neurotransmission phenotype. Finally, MCI subunit knockdowns led to profound cytological defects, including reduced NMJ growth and altered NMJ morphology. Mitochondria are essential for cellular bioenergetics and produce ATP through oxidative phosphorylation. Five multi-protein complexes achieve this task, and MCI is the largest. Impaired Mitochondrial Complex I subunits in humans are associated with disorders such as Parkinsons disease, Leigh syndrome, and cardiomyopathy. Together, our data present an analysis of Complex I in the context of synapse function and plasticity. We speculate that in the context of human MCI dysfunction, similar neuronal and synaptic defects could contribute to pathogenesis.

Identification of a novel proteomic Biomarker in Parkinson's Disease: Discovery and Replication in Blood, brain and CSF

Biomarkers to aid diagnosis and delineate progression of Parkinsons Disease (PD) are vital for targeting treatment in the early phases of disease. Here, we aim to discover a multi-protein panel representative of PD and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers. We used aptamer-based technology (SomaLogic) to measure proteins in 1,599 serum samples, 85 CSF samples and 37 brain tissue samples collected from two observational longitudinal cohorts (Oxford Parkinsons Disease Centre and Tracking Parkinsons) and the PD Brain Bank, respectively. Random forest machine learning was performed to discover new proteins related to disease status and generate multi-protein expression signatures with potential novel biomarkers. Differential regulation analysis and pathway analysis was performed to identify functional and mechanistic disease associations. The most consistent diagnostic classifier signature was tested across modalities (CSF AUC = 0.74, p-value = 0.0009; brain AUC = 0.75, p-value = 0.006; serum AUC = 0.66, p-value = 0.0002). In the validation dataset we showed that the same classifiers were significantly related to disease status (p-values < 0.001). Differential expression analysis and Weighted Gene Correlation Network Analysis (WGCNA) highlighted key proteins and pathways with known relationships to PD. Proteins from the complement and coagulation cascades suggest a disease relationship to immune response. The combined analytical approaches in a relatively large number of samples, across tissue types, with replication and validation, provides mechanistic insights into the disease as well as nominating a protein signature classifier that deserves further biomarker evaluation.

Polarized α-synuclein trafficking and transcytosis across Brain Endothelial Cells via Rab7-decorated carriers

Parkinsons disease is mainly caused by aggregation of alpha-synuclein (α-syn) in the brain. Exchange of α-syn between the brain and peripheral tissues could have important pathophysiological and therapeutic implications, but the trafficking mechanism of α-syn across the blood brain barrier (BBB) remains unclear. In this study, we therefore investigated uptake and transport mechanisms of α-syn monomers and oligomers across an in vitro BBB model system. Both α-syn monomers and oligomers were internalized by primary brain endothelial cells, with increased restriction of oligomeric over monomeric transport. To enlighten the trafficking route of monomeric α-syn in brain endothelial cells, we investigated co-localization of α-syn and intracellular markers of vesicular transport. Here, we observed the highest colocalization with clathrin, Rab7 and VPS35, suggesting a clathrin-dependent internalization, preferentially followed by a late endosome retromer-connected trafficking pathway. Furthermore, STED microscopy revealed monomeric α-syn trafficking via Rab7-decorated carriers. Knockdown of Caveolin1, VPS35, and Rab7 using siRNA did not affect monomeric α-syn uptake into endothelial cells. However, it significantly reduced transcytosis of monomeric α-syn in the luminal-abluminal direction, suggesting a polarized regulation of monomeric α-syn vesicular transport. Our findings suggest a direct role for Rab7 in polarized trafficking of monomeric α-syn across BBB endothelium, and the potential of Rab7 directed trafficking to constitute a target pathway for new therapeutic strategies against Parkinsons disease and related synucleinopathies.

The disorder of the iron metabolism as a possible mechanism for the development of neurodegeneration after new coronavirus infection of SARS-CoV-2

The involvement of the nervous system in the pathological process that occurs when COVID-19 is infected is becoming more and more obvious. The question of the possibility of the debut or progression of the already developed Parkinsonism syndrome in patients who have undergone COVID-19 is regularly raised. A large number of hypotheses are put forward to explain this relationship. It is assumed that a violation of iron metabolism in the brain may underlie the development and progression of neurodegenerative diseases, including after the new coronavirus infection SARS-CoV-2. The analysis of stu dies on the possible influence of iron metabolism disorders on the occurrence and mechanism of development of neurodegenerative diseases after infection with SARS-CoV-2 has been carried out. The processes of physiological maintenance of iron homeostasis, as well as the influence of physiological aging on the accumulation of iron in the central nervous system are described. The relationship between hyperferritinemia occurring in COVID-19 and ferroptosis as the basis of the neurodegenerative process in Parkinsons disease and Alzheimers disease is discussed. The main molecular mechanisms involved in ferroptosis are described. Examples of involvement of metal homeostasis disorders in the process of altering the structure of -synuclein, synthesis of -amyloid, hyperphosphorylated tau- protein are given. The causes of excessive iron accumulation in certain brain structures are discussed. The question of the possibility of using the assessment of changes in iron metabolism as a new biomarker of the progression of Parkinsons disease is analyzed. (1 figure, bibliography: 62 refs)

Comparative diagnostic sensitivity of the substantia nigra transcranial sonography and salivary gland biopsy in patients with Parkinson’s disease

Parkinsons disease is a chronic neurodegenerative disease, the diagnosis of which remains challenging at the early stages, although clinical diagnostic criteria are developed. The diagnostic accuracy is only 58% for patients at early Parkinsons disease stages. The sensitivity and specificity of transcranial sonography of the substantia nigra used for Parkinsons disease verification is about 85% and 71%, respectively. It has been shown that the aggregates of -synuclein in the nerve fibers in major salivary glands may be seen in Parkinsons disease patients. The availability of the salivary glands for morphological study made it possible to investigate the approaches of the in vivo histological diagnosis of Parkinsons disease based on the detection of -synuclein aggregates in the nerve fibers innervating the glands. Aim: To evaluate and compare the sensitivity of transcranial sonography of the substantia nigra and sublingual salivary gland biopsy. Materials and methods: Six patients with clinically verified Parkinsons disease were enrolled. Evaluation of the neurological state using special scales, transcranial sonography of the substantia nigra and sublingual salivary gland biopsy was performed. Results: Mean age of patients was 59 [58; 60.7] years, mean disease duration period was 5 [3; 7.75] years and the mean HoehnYahr stage was 2.25 [2; 2.5]. Hyperechogenicity of the substantia nigra was found in 3 of 6 patients and the substantia nigra sensitivity was shown to be 50%. Sublingual salivary gland biopsy was positive for -synuclein in 6 of 6 patients and the sensitivity of method was shown to be 100%. No adverse events after biopsy were registered. Conclusion: The sensitivity of sublingual salivary gland biopsy was higher than those of transcranial sonography of the substantia nigra, which indicates the prospect of using the biopsy method as a more sensitive diagnostic tool in Parkinsons disease (1 table, bibliography: 19 refs)

Survival and risk factors for premature mortality in patients with parkinson’s disease

Aim. To assess the survival rate and risk factors for premature mortality in patients with Parkinsons disease in Baku. Material and research methods. The observation was carried out retrospectively, information was collected on all patients (110 patients) in whom the diagnosis of Parkinsons disease was first established in 20092010. These patients are provided with drugs free of charge, which made it possible to provide them with diagnostic monitoring in polyclinics. During 20102019, 94 patients with a diagnosis of Parkinsons disease died. All medical death certificates were selected for analysis. The diagnoses in column a of these documents were accepted as direct causes of death, regardless of the presence or absence of a causal relationship of these diagnoses with Parkinsons disease. Therefore, the reported cases were interpreted not as death due to Parkinsons disease, but as the death of a patient diagnosed with Parkinsons disease. Results. Noteworthy is the prevalence of men (72.7%) and people without dementia (70.9%) among patients. Within 10 years, 85.5% of patients died from various causes. The immediate causes of death were acute cerebrovascular accidents (36.2%) and acute myocardial infarction (24.5%). The annual survival rate of the observed patients was high (94%; 95% confidence interval 51100%). The five-year survival rate is 76% (95% confidence interval 42100%). Conclusions. (1) The survival rate of patients with Parkinsons disease within 10 years after the onset of signs ranges from 0.94 to 0.41 (five-year survival rate is 0.76). (2) The immediate causes of mortality in patients with Parkinsons disease were cerebrovascular accidents (36.2%), myocardial infarction (24.5%), pulmonary embolism (11.7%), pneumonia (10.6%) and others (17%). (3) The effect of age of onset and signs of Parkinsons disease, gender, comorbidity and dementia on survival is statistically significant (p 0.05).

Gut bacterial tyrosine decarboxylase associates with clinical variables in a longitudinal cohort study of Parkinsons disease

Gut microbiota influences the clinical response of a wide variety of orally administered drugs. However, the underlying mechanisms through which drug–microbiota interactions occur are still obscure. Previously, we reported that tyrosine decarboxylating (TDC) bacteria may restrict the levels of levodopa reaching circulation in patients with Parkinson’s disease (PD). We observed a significant positive association between disease duration and the abundance of the bacterial tdc-gene. The question arises whether increased exposure to anti-PD medication could affect the abundance of bacterial TDC, to ultimately impact drug efficacy. To this end, we investigated the potential association between anti-PD drug exposure and bacterial tdc-gene abundance over a period of 2 years in a longitudinal cohort of PD patients and healthy controls. Our data reveal significant associations between tdc-gene abundance, several anti-PD medications, including entacapone, rasagiline, pramipexole, and ropinirole but not levodopa, and gastrointestinal symptoms, warranting further research on the effect of anti-PD medication on microbial changes and gastrointestinal function.

LOWER URINARY TRACT SYMPTOMS IN NIGERIAN MEN WITH PARKINSONS DISEASE

Introduction: Parkinsons disease (PD) is the commonest age related motoric neurodegenerative disease. It results from the destruction of dopaminergic cell in the substantial nigra in the midbrain. In addition to the typical motor Parkinsonism symptoms, non -motor manifestations affect multiple organs including the lower urinary tract and contribute to worsening the overall quality of life. The objective of this study is to highlight the bother from lower urinary tract symptoms in patients with PD and determine the relationship between the lower urinary symptoms and severity of PD. Materials and Methods: This is a descriptive cross-sectional study in patients with clinically diagnosed PD that were managed by the Neurology Unit, Neurology Unit, Department of Medicine University of Port Harcourt Teaching Hospital, Port Harcourt, Rivers State, Nigeria. They all filled the International Prostate Symptom Score and Quality of Life form. The severity of PD in each patient was assessed using Unified Parkinsons Disease Rating Scale (UPDRS). The data obtained was analyzed using SPSS Version 20. Results: There were 22 patients aged between 25-87years with a mean age of 59.36 ±15.58years. Nocturia (90.90%), frequency (59.10%) and urgency (59.10%) were the commonest LUTS, while straining was the least frequent (22.70 %). Majority had mild (59.09%)and moderate (27.27%) symptoms. There was a strong association between total IPSSand QoL scores that was statistically significant (p<0.0001 r= +0.859). The degree of bother from LUTS, evaluated with the IPSS questionnaire was associated with worsening of PD symptoms assessed with UPDRS (p=0.012). There was a moderate positive correlation between the severity of PD and the degree of bother from LUTS in PD patients (r=+0.527) Conclusions: Irritative symptoms are very common in Parkinsons disease, with nocturia the commonest. There was a moderate positive correlation between the severity of PD and the degree of bother from LUTS. The IPSS questionnaire could be used in evaluating urinary dysfunction in PD patients in both genders.