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Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

Background: Psoriasis is a chronic skin disorder affecting 2–3% of the global population, and is associated with several comorbidities, including psychiatric disorders. This study aimed to identify factors influencing anxiety, depression, and quality of life (QoL) in patients with psoriasis. Methods: This observational study included 112 patients diagnosed with psoriasis. Dermatological and psychiatric assessments were conducted using Psodisk, the Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Symptom Checklist-90-Revised (SCL-90-R), and 36-Item Short Form Health Survey (SF-36). Descriptive statistics, correlation analyses, and multivariate regression models were employed. Results: The sample was predominantly middle-aged males (mean age 48.91 years). Females (p < 0.001), patients with arthritis (p < 0.05), and those with a sedentary lifestyle (p < 0.05) showed higher anxiety and depression scores. Psodisk subscales significantly correlated with psychiatric symptoms and QoL measures (p < 0.001). Pain (B: 0.63, p < 0.05; B: −2.03, p < 0.01) and sleep disturbances (B: 0.68, p < 0.01; B: 0.60, p < 0.01; B: −1.46, p < 0.01; B: −1.57, p < 0.05; B: 3.91, p < 0.05) emerged as major predictors of poor mental health and reduced QoL. Conclusions. The study underscores the complex relationship between psoriasis, psychiatric comorbidities, and QoL. Key factors exacerbating anxiety and depression include female gender, arthritis, and sedentary lifestyle. Comprehensive management of psoriasis should address both dermatological and psychological aspects, with a focus on pain relief and improving sleep quality to enhance overall patient well-being.

In Parkinson's disease (PD), post-mortem studies in affected brain regions have demonstrated a decline in mitochondrial number and function. This combined with many studies in cell and animal models suggest that mitochondrial dysfunction is central to PD pathology. We and others have shown that the mitochondrial protein deacetylase, SIRT3, has neurorestorative effects in PD models. In this study, to determine whether there is a link between PD pathology and SIRT3, we analysed SIRT3 levels in human subjects with PD, and compared to age-matched controls. In the SNc of PD subjects, SIRT3 was reduced by 56.8 ± 15.5% compared to control, regardless of age (p

We recently identified a truncated and phosphorylated form of α-synuclein, pα-syn*, as a key neurotoxic α-synuclein species found in cultured neurons, as well as in mouse and Parkinson's disease patients' brains. Small pα-syn* aggregates localize to mitochondria and induce mitochondrial damage and fragmentation. Herein, we investigated the molecular basis of pα-syn*-induced toxicity. By immunofluorescence, we found phosphorylated MKK4, JNK, ERK5 and p38 MAPKs in pα-syn* inclusions. pJNK colocalized with pα-syn* at mitochondria and mitochondria-associated ER membranes where it was associated with BiP and pACC1, markers for the ER and energy deprivation, respectively. We also found that pα-syn* aggregates are tightly associated with small ptau aggregates of similar size. Pα-syn*/ptau inclusions localized to areas of mitochondrial damage and to mitophagic vesicles, showing their role in mitochondrial toxicity, mitophagy induction and their removal along with damaged mitochondrial fragments. Several MAPKs may act cooperatively to phosphorylate tau, notably JNK, p38 and GSK3β, a non-MAPK that was also found phosphorylated in the vicinity of pα-syn*/ptau aggregates. These results add insight into the mechanisms by which pα-syn* exerts its toxic effects that include the phosphorylation of several kinases of the MAPK pathway, as well as the formation of ptau at the mitochondrial membrane, likely contributing to mitotoxicity. Thus pα-syn* appears to be the trigger of a series of kinase mediated pathogenic events and a link between α-syn pathology and tau, another protein known to aggregate in Parkinson's disease and other synucleinopathies.

Previous studies have indicated that vitamin (Vit) D deficiency is frequent in psychiatric patients, regardless of diagnostic category. We aimed to assess whether acute psychiatric relapses in inpatients was associated with Vit D deficiency compared to stabilized outpatients. The cohort (152 total patients, 75 males and 77 females) had a mean age of 47.3 ± 14.4 years at admission and was grouped according to psychiatric diagnosis. Psychopathological symptom severity was assessed by the Brief Psychiatric Rating Scale (BPRS), a multidimensional symptom inventory. Total calcium serum levels were measured using standard laboratory methods, while plasma levels of 25-OH-Vit D and parathyroid hormone (PTH) were measured by automated chemiluminescence immunoassays. The psychiatric inpatient subgroup showed a significant difference in serum levels of 25-OH-Vit D and PTH (p < 0.001). Correlation analysis between serum levels of 25-OH-Vit D and BPRS total and subitem scores indicated a significantly negative relationship. In addition, linear regression analysis evidenced that the inpatient condition might predict low PTH and 25-OH-Vit D serum levels. Hospitalized psychiatric patients are at increased risk for Vit D deficiency regardless of their diagnostic categories. The mechanism underlying the association between acute psychiatric relapses and Vit D deficiency remains unclear. Therefore, screening for Vit D deficiency should pertain to the health assessment of patients with major psychiatric disorders.

Parkinson’s disease (PD) is a progressive neurodegenerative disease that impairs movement as well as causing multiple other symptoms such as autonomic dysfunction, rapid eye movement (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) and loss of dopamine terminals in the striatum contribute to characteristic motor features. Although therapies ease the symptoms of PD, there are no treatments to slow its progression. Accumulating evidence suggests that synaptic impairments and axonal degeneration precede neuronal cell body loss. Early synaptic changes may be a target to prevent disease onset and slow progression. Imaging of PD patients with radioligands, post-mortem pathologic studies in sporadic PD patients, and animal models of PD demonstrate abnormalities in presynaptic terminals as well as postsynaptic dendritic spines. Dopaminergic and excitatory synapses are substantially reduced in PD, and whether other neuronal subtypes show synaptic defects remains relatively unexplored. Genetic studies implicate several genes that play a role at the synapse, providing additional support for synaptic dysfunction in PD. In this review article we: (1) provide evidence for synaptic defects occurring in PD before neuron death; (2) describe the main genes implicated in PD that could contribute to synapse dysfunction; and (3) show correlations between the expression of Snca mRNA and mouse homologs of PD GWAS genes demonstrating selective enrichment of Snca and synaptic genes in dopaminergic, excitatory and cholinergic neurons. Altogether, these findings highlight the need for novel therapeutics targeting the synapse and suggest that future studies should explore the roles for PD-implicated genes across multiple neuron types and circuits.

Parkinson's disease (PD) is defined by motor symptoms such as tremor at rest, bradykinesia, postural instability, and stiffness. In addition to the classical motor defects that define PD, up to 80% of patients experience cognitive changes and psychiatric disturbances, referred to as PD dementia (PDD). Pathologically, PD is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein. Much of PD research has focused on the role of α-synuclein aggregates in degeneration of SNpc dopamine neurons because of the impact of loss of striatal dopamine on the classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the cortex and limbic brain regions such as the amygdala, which may contribute to non-motor phenotypes. Little is known about the consequences of α-synuclein inclusions in these brain regions, or in neuronal subtypes other than dopamine neurons. This project expands knowledge on how α-synuclein inclusions disrupt behavior, specifically non-motor symptoms of synucleinopathies. We show that bilateral injections of fibrils into the striatum results in robust bilateral α-synuclein inclusion formation in the cortex and amygdala. Inclusions in the amygdala and prefrontal cortex primarily localize to excitatory neurons, but unbiased stereology shows no significant loss of neurons in the amygdala or cortex. Fibril injected mice show defects in a social dominance behavioral task and fear conditioning, tasks that are associated with prefrontal cortex and amygdala function. Together, these observations suggest that seeded α-synuclein inclusion formation impairs behaviors associated with cortical and amygdala function, without causing cell loss, in brain areas that may play important roles in the complex cognitive features of PDD.

Lewy bodies and Lewy neurites composed primarily of α-synuclein characterize synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Despite decades of research on the impact of α-synuclein, little is known how abnormal inclusion made of this protein compromise neuronal function. Emerging evidence suggests that defects in axonal transport caused by aggregated α-synuclein contribute to neuronal dysfunction. These defects appear to occur well before the onset of neuronal death. Susceptible neurons in PD such as dopamine neurons with long elaborate axons may be particularly sensitive to abnormal axonal transport. Axonal transport is critical for delivery of signaling molecules to the soma responsible for neuronal differentiation and survival. In addition, axonal transport delivers degradative organelles such as endosomes and autophagosomes to lysosomes located in the soma to degrade damaged proteins and organelles. Identifying the molecular mechanisms by which axonal transport is impaired in PD and DLB may help identify novel therapeutic targets to enhance neuron survival and even possibly prevent disease progression. Here, we review the evidence that axonal transport is impaired in synucleinopathies, and describe potential mechanisms by which contribute to these defects.

Proteinaceous inclusions in neurons, composed primarily of α-synuclein, define the pathology in several neurodegenerative disorders. Neurons can internalize α-synuclein fibrils that can seed new inclusions from endogenously expressed α-synuclein. The factors contributing to the spread of pathology and subsequent neurodegeneration are not fully understood, and different compositions and concentrations of fibrils have been used in different hosts. Here, we systematically vary the concentration and length of well-characterized α-synuclein fibrils and determine their relative ability to induce inclusions and neurodegeneration in different hosts (primary neurons, C57BL/6 J and C3H/HeJ mice, and Sprague Dawley rats). Using dynamic-light scattering profiles and other measurements to determine fibril length and concentration, we find that femptomolar concentrations of fibrils are sufficient to induce robust inclusions in primary neurons. However, a narrow and non-linear dynamic range characterizes fibril-mediated inclusion induction in axons and the soma. In mice, the C3H/HeJ strain is more sensitive to fibril exposures than C57BL/6 J counterparts, with more inclusions and dopaminergic neurodegeneration. In rats, injection of fibrils into the substantia nigra pars compacta (SNpc) results in similar inclusion spread and dopaminergic neurodegeneration as injection of the fibrils into the dorsal striatum, with prominent inclusion spread to the amygdala and several other brain areas. Inclusion spread, particularly from the SNpc to the striatum, positively correlates with dopaminergic neurodegeneration. These results define biophysical characteristics of α-synuclein fibrils that induce inclusions and neurodegeneration both in vitro and in vivo, and suggest that inclusion spread in the brain may be promoted by a loss of neurons.

We analyzed the molecular mechanisms involved in the acquisition and maturation of dopaminergic (DA) neurons generated in vitro from rat ventral mesencephalon (MES) cells in the presence of mitogens or specific signaling molecules. The addition of basic fibroblast growth factor (bFGF) to MES cells in serum-free medium stimulates the proliferation of neuroblasts but delays DA differentiation. Recombinant Sonic hedgehog (SHH) protein increases up to three fold the number of tyrosine hydroxylase (TH)-positive cells and their differentiation, an effect abolished by anti-SHH antibodies. The expanded cultures are rich in nestin-positive neurons, glial cells are rare, all TH+ neurons are DA, and all DA and GABAergic markers analyzed are expressed. Adding ascorbic acid to bFGF/SHH-treated cultures resulted in a further five- to seven-fold enhancement of viable DA neurons. This experimental system also provides a powerful tool to generate DA neurons from single embryos. Our strategy provides an enriched source of MES DA neurons that are useful for analyzing molecular mechanisms controlling their function and for experimental regenerative approaches in DA dysfunction.

Abnormal neurofilament aggregates are pathological hall-mark of most neurodegenerative diseases, although their pathogenic role remains unclear. Increased expression of medium neurofilament (NFM) is an early molecular marker of wobbler mouse, an animal model of motoneuron disease. In the wr/wr, a vacuolar neuronal degeneration (VND) starts at 15 days postnatally, selectively in cervical spinal cord and brain stem motoneurons. Here we show that nfm gene hyperexpression is restricted to the aforementioned motoneurons and is specific for wr mutation. NF proteins accumulate in wr/wr before VND. wr/+ mice, which are asymptomatic, show intermediate NF accumulation between wr/wr and +/+ littermates, suggesting a gene dosage dependence of the wobbler pathology. Altogether our data indicate that NF hyperexpression and regionalized motoneuron degeneration are linked to the wr mutation, although with a still unknown relationship to the mutant gene activity.