Neuromelanin-sensitive magnetic resonance imaging: Possibilities and promises as an imaging biomarker for Parkinson's disease.

Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder characterized by both motor and non-motor symptoms resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus (LC). The current diagnosis of PD primarily relies on motor symptoms, often leading to diagnoses in advanced stages, where a significant portion of SNpc dopamine neurons has already succumbed. Therefore, the identification of imaging biomarkers for early-stage PD diagnosis and disease progression monitoring is imperative. Recent studies propose that neuromelanin-sensitive magnetic resonance imaging (NM-MRI) holds promise as an imaging biomarker. In this review, we summarize the latest findings concerning NM-MRI characteristics at various stages in patients with PD and those with atypical parkinsonism. In conclusion, alterations in neuromelanin within the LC are associated with non-motor symptoms and prove to be a reliable imaging biomarker in the prodromal phase of PD. Furthermore, NM-MRI demonstrates efficacy in differentiating progressive supranuclear palsy (PSP) from PD and multiple system atrophy with predominant parkinsonism. The spatial patterns of changes in the SNpc can be indicative of PD progression and aid in distinguishing between PSP and synucleinopathies. We recommend that patients with PD and individuals at risk for PD undergo regular NM-MRI examinations. This technology holds the potential for widespread use in PD diagnosis.

Therapeutic Effects of Selenium on Alpha-Synuclein Accumulation in Substantia Nigra Pars Compacta in a Rat Model of Parkinson's Disease: Behavioral and Biochemical Outcomes.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the accumulation of accumulated alpha-synuclein (α-Syn) in substantia nigra. Research has shown that selenium (Se) can protect neural cells through the actions of selenoproteins, including selenoprotein P (SelP) and selenoprotein S (SelS), which participate in endoplasmic reticulum-associated protein degradation (ERAD). In this study, we investigated the potential protective role of Se in a pre-clinical PD rat model.We aimed to evaluate the therapeutic effects of Se administration in the 6-hydroxydopamine (6-OHDA) induced unilateral rat PD model. Male Wistar rats were utilised for unilateral PD animal model which were subjected to stereotaxic surgery and injected with 20 µg 6-OHDA/5 µl 0.2% ascorbate saline. After confirming the model, the rats were intraperitoneally injected with 0.1, 0.2, and 0.3 mg/kg of sodium selenite for 7 days. We then performed behavioral tests, including apomorphine-induced rotation, hanging, and rotarod tests. Following sacrifice, we analysed the substantia nigra area of the brain and serum for protein quantification, element analysis, and gene expression analysis.Our results indicate that the administration of 0.3 mg/kg of Se improved the motor deficiency in hanging, rotarod, and apomorphine-induced rotational tests. While there was no significant improvement in the expression of α-Syn, Se increased the expression of selenoproteins. Additionally, levels of selenoproteins, Se, and α-Syn both brain and serum were re-established by the treatment, suggesting the role of Se on the α-Syn accumulation. Furthermore, Se improved PD-induced biochemical deficits by increasing the levels of SelS and SelP (p<0.005).In conclusion, our findings suggest that Se may have a protective role in PD. 0.3 mg/kg dosage of Se increased the expression of selenoproteins, reduced the accumulation of α-Syn in the brain, and improved PD-induced motor deficits. These results suggest that Se may be a potential therapeutic option for PD treatment.

The effect of SARS-CoV-2 on the development of Parkinson's disease: the role of α-synuclein.

The current coronavirus disease 2019 (COVID-19) can lead to various neurological complications in infected people. These neurological effects include problems in both central nervous system (CNS) and peripheral nervous system (PNS). Hyposmia, a PNS symptom of COVID-19, frequently manifests in the early stages of Parkinson's disease (PD) and serves as an early warning sign of the condition. In addition, the olfactory system is recognized as an early site for the onset of α-synuclein pathology, the pathological hallmark of PD. PD is characterized by accumulation and aggregation of misfolded α-synuclein (α-Syn) into Lewy bodies and Lewy neurites, resulting in the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Previous research has also shown the involvement of α-Syn in the innate immune response following viral infections. Consequently, the potential link between viral infections and development of PD has gained attention in recent years. However, it's still too early to definitively conclude whether COVID-19 can cause Parkinsonism. Nevertheless, we can explore the likelihood of this connection by examining past studies and possible mechanisms to better understand how COVID-19 might potentially lead to PD following the infection. Based on the various pieces of evidence discussed in this review, we can infer that SARS-CoV-2 promotes the aggregation of α-Syn and, ultimately, leads to PD through at least two mechanisms: the stable binding of the S1 protein to proteins prone to aggregation like α-Syn, and the upregulation of α-Syn as part of the immune response to the infection.

A genetic and transcriptomic assessment of the KTN1 gene in Parkinson's disease risk.

Parkinson's disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson's Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to unaffected individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

Mitochondrial homeostasis regulation: A promising therapeutic target for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies (LBs) or Lewy neurites (LNs) which consist of α-synuclein (α-syn) and a complex mix of other biomolecules. Mitochondrial dysfunction is widely believed to play an essential role in the pathogenesis of PD and other related neurodegenerative diseases. But mitochondrial dysfunction is subject to complex genetic regulation. There is increasing evidence that PD-related genes directly or indirectly affect mitochondrial integrity. Therefore, targeted regulation of mitochondrial function has great clinical application prospects in the treatment of PD. However, lots of PD drugs targeting mitochondria have been developed but their clinical therapeutic effects are not ideal. This review aims to reveal the role of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases based on the mitochondrial structure and function, which may highlight potential interventions and therapeutic targets for the development of PD drugs to recover mitochondrial dysfunction in neurodegenerative diseases.

Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease.

Studying animal models furthers our understanding of Parkinson's disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson's disease in mice.

A Novel NOX Inhibitor Alleviates Parkinson's Disease Pathology in PFF-Injected Mice.

Oxidative stress-mediated damage is often a downstream result of Parkinson's disease (PD), which is marked by sharp decline in dopaminergic neurons within the nigrostriatal regions of the brain, accounting for the symptomatic motor deficits in patients. Regulating the level of oxidative stress may present a beneficial approach in preventing PD pathology. Here, we assessed the efficacy of a nicotinamide adenine phosphate (NADPH) oxidase (NOX) inhibitor, an exogenous reactive oxygen species (ROS) regulator synthesized by Aptabio therapeutics with the specificity to NOX-1, 2 and 4. Utilizing N27 rat dopaminergic cells and C57Bl/6 mice, we confirmed that the exposures of alpha-synuclein preformed fibrils (PFF) induced protein aggregation, a hallmark in PD pathology. In vitro assessment of the novel compound revealed an increase in cell viability and decreases in cytotoxicity, ROS, and protein aggregation (Thioflavin-T stain) against PFF exposure at the optimal concentration of 10 nM. Concomitantly, the oral treatment alleviated motor-deficits in behavioral tests, such as hindlimb clasping, rotarod, pole, nesting and grooming test, via reducing protein aggregation, based on rescued dopaminergic neuronal loss. The suppression of NOX-1, 2 and 4 within the striatum and ventral midbrain regions including Substantia Nigra compacta (SNc) contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD.

Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease.

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

Collateral projections from the ventral tegmental area/substantia nigra pars compacta to the nucleus accumbens and insular cortex in the rat.

Midbrain dopaminergic (DAergic) regions including ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are involved in diverse brain functions. Previous studies demonstrated that the VTA/SNc to nucleus accumbens (NAc) pathway is critical in reward and motivation. Moreover, DAergic innervations within the insular cortex (IC) are reported to play important roles in pain regulation. To investigate whether VTA/SNc sends collateral projections to NAc and IC, we injected retrograde tracer Fluoro-Gold (FG) into the NAc and Fluorescent retrograde tracer beads (RetroBeads) into the ipsilateral IC in rats. Then, to detect whether collateral projection neurons participate in neuropathic pain, parts of the rats received the spare nerve injury (SNI) surgery. The immunofluorescence staining results showed that FG, RetroBeads, and FG/RetroBeads double-labeled neurons were distributed in the VTA/SNc bilaterally with an ipsilateral predominance. The proportion of FG/RetroBeads double-labeled neurons to the total number of FG and RetroBeads-labeled neurons was 16.7% and 30.3%, respectively. About 90.3% of FG/RetroBeads double-labeled neurons showed DAergic neuron marker tyrosine hydroxylase (TH)-immunoreactive (IR), whereas, only 7.5% exhibited a subset of GABAergic inhibitory projection neuron marker parvalbumin (PV)-IR. One week after SNI, about 53.1% and 33.6% of FG- and RetroBeads-labeled neurons were FG/Fos- and RetroBeads/Fos-IR neurons, respectively. Finally, about 35.9% of the FG/RetroBeads double-labeled neurons showed Fos-IR. The present study indicates that parts of DAergic and PV-IR GABAergic neurons in the VTA/SNc send collateral projections to both NAc and IC, which are activated under SNI-induced neuropathic pain, and probably contribute to the regulation of nociception.

Parkinson's Disease: Exploring Different Animal Model Systems.

Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson's disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson's disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient's motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson's diseases. These include animal systems with induction of Parkinson's, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson's disease animal model systems and their applications and limitations.

Uncovering Novel Therapeutic Targets for Parkinson's Disease.

Parkinson's disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical manifestations of PD appear in a much later stage and include rigidity, tremors, akinesia, and gait dysfunction. There are also nonmotor symptoms like GI and olfactory dysfunction. However, they cannot be considered for diagnosis of the disease, as they are unspecific. PD pathogenesis is mainly characterized by deposits of inclusion bodies on dopaminergic (DA) neurons in substantia nigra pars compacta region (SNpc) of the brain. The major component of these inclusion bodies, are α-synuclein aggregates. α-Synuclein undergoes misfolding and oligomerization to form aggregates and fibrils. These aggregates gradually propagate PD pathology. Other prominent features of this pathological development include mitochondrial dysfunction, neuroinflammation, oxidative stress, and impaired autophagy. These all contribute to neuronal degeneration. Besides this, there are many underlying factors which influence these processes. These factors comprise molecular proteins and signaling cascades. In this review, we have listed out underexplored molecular targets that may aid in development of neoteric and advanced therapeutics.

Insights into Neurodegeneration in Parkinson's Disease from Single-Cell and Spatial Genomics.

Parkinson's disease (PD) is pathologically defined by the death of dopaminergic (DA) neurons within the pars compacta of the substantia nigra. To date, the cause of this multifaceted disease remains largely unclear, which may contribute in part to a current lack of disease-modifying therapies. Recent advances in single-cell and spatial genomic profiling tools have provided powerful new ways to measure cellular state changes in brain diseases. Here, we describe how these tools have offered insight into these complex disorders and highlight a recently performed comprehensive study of DA neuron susceptibility in PD. The data generated by this recent work provide evidence for the role of specific pathways and common genetic variants resulting in the loss of a critical DA subtype in PD. We conclude by outlining a set of basic and translational opportunities that arise from those data and insights gathered from this work. © 2023 International Parkinson and Movement Disorder Society.

DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms.

Parkinson's disease (PD) is a neurodegenerative disorder with typical motor symptoms. Recent studies have suggested that excessive GABA from reactive astrocytes tonically inhibits dopaminergic neurons and reduces the expression of tyrosine hydroxylase (TH), the key dopamine-synthesizing enzyme, in the substantia nigra pars compacta (SNpc). However, the expression of DOPA decarboxylase (DDC), another dopamine-synthesizing enzyme, is relatively spared, raising a possibility that the live but non-functional TH-negative/DDC-positive neurons could be the therapeutic target for rescuing PD motor symptoms. However, due to the absence of a validated DDC-specific promoter, manipulating DDC-positive neuronal activity has not been tested as a therapeutic strategy for PD. Here, we developed an AAV vector expressing mCherry under rat DDC promoter (AAV-rDDC-mCherry) and validated the specificity in the rat SNpc. Modifying this vector, we expressed hM3Dq (Gq-DREADD) under DDC promoter in the SNpc and ex vivo electrophysiologically validated the functionality. In the A53T-mutated alpha-synuclein overexpression model of PD, the chemogenetic activation of DDC-positive neurons in the SNpc significantly alleviated the parkinsonian motor symptoms and rescued the nigrostriatal TH expression. Altogether, our DDC-promoter will allow dopaminergic neuron-specific gene delivery in rodents. Furthermore, we propose that the activation of dormant dopaminergic neurons could be a potential therapeutic strategy for PD.

Preservation of dendritic D2 receptor transmission in substantia nigra dopamine neurons with age.

Substantia nigra pars compacta (SNc) dopamine neurons are required for voluntary movement and reward learning, and advanced age is associated with motor and cognitive decline. In the midbrain, D2-type dopamine receptors located at dendrodendritic synapses between dopamine neurons control cell firing through G protein-activated potassium (GIRK) channels. We previously showed that aging disrupts dopamine neuron pacemaker firing in mice, but only in males. Here we show that the amplitude of D2-receptor inhibitory postsynaptic currents (D2-IPSCs) are moderately reduced in aged male mice. Local application of dopamine revealed a reduction in the amplitude of the D2-receptor currents in old males compared to young, pointing to a postsynaptic mechanism. Further experiments indicated that reduced D2 receptor signaling was not due to a general reduction in GIRK channel currents or degeneration of the dendritic arbor. Kinetic analysis showed no differences in D2-IPSC shape in old versus young mice or between sexes. Potentiation of D2-IPSCs by corticotropin releasing factor (CRF) was also not affected by age, indicating preservation of one mechanism of plasticity. These findings have implications for understanding dopamine transmission in aging, and reduced D2 receptor inhibition could contribute to increased susceptibility of males to SNc dopamine neuron degeneration in Parkinson's disease.

C/EBPß Regulates TFAM Expression, Mitochondrial Function and Autophagy in Cellular Models of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Since there are only symptomatic treatments available, new cellular and molecular targets involved in the onset and progression of this disease are needed to develop effective treatments. CCAAT/Enhancer Binding Protein ß (C/EBPß) transcription factor levels are altered in patients with a variety of neurodegenerative diseases, suggesting that it may be a good therapeutic target for the treatment of PD. A list of genes involved in PD that can be regulated by C/EBPß was generated by the combination of genetic and in silico data, the mitochondrial transcription factor A (TFAM) being among them. In this paper, we observed that C/EBPß overexpression increased TFAM promoter activity. However, downregulation of C/EBPß in different PD/neuroinflammation cellular models produced an increase in TFAM levels, together with other mitochondrial markers. This led us to propose an accumulation of non-functional mitochondria possibly due to the alteration of their autophagic degradation in the absence of C/EBPß. Then, we concluded that C/EBPß is not only involved in harmful processes occurring in PD, such as inflammation, but is also implicated in mitochondrial function and autophagy in PD-like conditions.

Association of Glial Activation and α-Synuclein Pathology in Parkinson's Disease.

The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.

Morpho-Functional Changes of Nigral Dopamine Neurons in an α-Synuclein Model of Parkinson's Disease.

BACKGROUND: The accumulation of α-synuclein (α-syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α-syn-dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α-syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α-syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression. OBJECTIVES: We aimed to determine the consequences of a prolonged α-syn overexpression on somatodendritic morphology and functions of SNpc DA neurons. METHODS: We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch-clamp recordings, and in vivo DA microdialysis measurements in a 12- to 13-month-old transgenic rat model overexpressing the full-length human α-syn (Snca+/+ ) and age-matched wild-type rats. RESULTS: Aged Snca+/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/inactivating voltage-gated K+ channels and Ca2+ - and voltage-activated large conductance K+ channels. These intrinsic currents underlie the repolarization/afterhyperpolarization phase of action potentials, thus affecting neuronal excitability. CONCLUSIONS: Besides clarifying α-syn-induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Vitamin D3 promotes oligodendrogenesis and modulates synucleinopathy in lead-induced nigral pars compacta neurotoxicity in rats.

BACKGROUND: Lead-induced neurotoxicity was marked with locomotor and Parkinsonian-like changes. Oligodendrocytes and synucleinopathy were signed to in the pathophysiology of some neurodegenerative diseases. Vitamin D3's (D3) role in substantia nigra pars compacta (SNpc) disorders is debated between neuroscientists. The aim of the study was to investigate lead-induced SNpc neurotoxic changes and explore the possible neuroprotective role of D3 and the possible involvement of oligodendrocytes and α-synuclein. MATERIALS AND METHODS: This study included 40 adult Wistar rats assigned into four equal groups: control, lead (Pb) (in drinking water, 1,000 mg/L), Pb + D3 (D3 injection, 1,000 IU/kg IM; 3 days/week), and D3. After 8 weeks, the rats were sacrificed, and their midbrain underwent biochemical and immunoblotting analysis. Midbrain paraffin blocks were stained for histological and immunohistochemical assessment. RESULTS: Lead (Pb) had increased significantly (p < 0.05) nigral α-synuclein and caspase-11 by immunoblotting analysis. Histologically, it induced neurodegeneration in SNpc and significantly decreased neuronal cell density by cresyl violet staining. Pb also significantly reduced SNpc tyrosine hydroxylase immunoreaction, significantly elevated glial fibrillatory acid protein (GFAP) and α-synuclein immunoreaction associated with a mild but significant increase in caspase-3. In the Pb + D3 group, all the previous deleterious changes were significantly alleviated in addition to significant upregulation of anti-oligodendrocytes immunoexpression. CONCLUSIONS: Lead (Pb) may induce SNpc neurotoxicity presumably via activation of caspase-11 and α-synuclein. D3 may modulate this neurotoxicity probably through an oligodendrogenic effect.

Deciphering Intertwined Molecular Pathways Underlying Metabolic Syndrome Leading to Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that gradually develops over time in a progressive manner. The main culprit behind the disease pathology is dopaminergic deficiency in Substantia nigra Pars Compacta (SNpc) due to neuronal degeneration. However, there are other factors that are not only associated with it but also somehow responsible for inception of pathology. Metabolic syndrome is one such risk factor for PD. Metabolic syndrome is a cluster of diseases mainly including diabetes, hypertension, obesity, and hyperlipidemia which pose a risk for developing cardiovascular disorders. All of these disorders have their own pathological pathways that intertwine with PD pathology. This leads to alpha-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress which are facets in initiating PD pathology. Although few reports are available, this area is underexplored and has contradictory views. Hence, further studies are needed in order to establish a definite relationship between PD and metabolic syndrome. In this review, we aim to elucidate the molecular mechanisms to confirm the association between them and pave the way for potential repurposing of therapies.

Effect of sex and autism spectrum disorder on oxytocin receptor binding and mRNA expression in the dopaminergic pars compacta of the human substantia nigra.

Oxytocin is an endogenous neuropeptide hormone that influences social behaviour and bonding in mammals. Variations in oxytocin receptor (OXTR) expression may play a role in the social deficits seen in autism spectrum disorder. Previous studies from our laboratory found a dense population of OXTR in the human substantia nigra (SN), a basal ganglia structure in the midbrain that is important in both movement and reward pathways. Here, we explore whether differences in OXTR can be identified in the dopaminergic SN pars compacta of individuals with autism. Postmortem human brain tissue specimens were processed for OXTR autoradiography from four groups: males with autism, females with autism, typically developing (TD) males and TD females. We found that females with autism had significantly lower levels of OXTR than the other groups. To examine potential gene expression differences, we performed in situ hybridization in adjacent slides to visualize and quantify OXTR mRNA as well as mRNA for tyrosine hydroxylase. We found no differences in mRNA levels for either gene across the four groups. These results suggest that a dysregulation in local OXTR protein translation or increased OXTR internalization/recycling may contribute to the differences in social symptoms seen in females with autism. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.