Alpha-synuclein

Alpha synuclein and Lrrk2 are key players in Parkinson's disease and related disorders, but their normal role has been confusing and controversial. Data from acute gene-editing based knockdown, followed by functional assays, will be presented.

…and neuronal accumulation of alpha-synuclein (a-syn). The ‘brain-first vs body-first’ hypothesis of PD proposes that a-syn pathology begins in the brain then spreads to the gut, or conversely begins in the gut then spreads to the brain, via the peripheral nervous system. The gut microbiota has been implicated in PD, and early dysbiosis and a-syn accumulation in the gut have been reported in ‘body-first’ PD. However, it is unclear if these events also occur in ‘brain-first’ PD. Here we investigated whether alterations

…synaptic accumulation of pathological alpha-synuclein in synapses in brain tissue from people who died with Dementia with Lewy Bodies (DLB), but whether this occurs in Parkinson’s disease (PD), a related neurodegenerative synucleinopathy, remains unknown, as do mechanisms of synapse degeneration in these diseases. Oligomeric tau has been implicated in synaptotoxicity in tauopathies, including Alzheimer’s disease, and growing evidence supports that the co-aggregation of different

Parkinson's disease has been characterized by the significant role that alpha-synuclein and immune activation play in driving disease progression. Moreover, the immunogenicity of alpha-synuclein-derived epitopes in driving both innate and adaptive immunity has been discovered in prodromal Parkinson's disease. Despite these findings, the mechanistic role of the immune system in contributing to disease ontogenesis remains unknown. Recent evidence has identified alpha-synuclein as a candidate biomarker, with seed amplification assays yielding high sensitivity for sporadic cases of the disease. Pe

…(PD) induced by inoculating human alpha-synuclein into the olfactory bulb to trigger alpha-synucleinopathy in wildtype mice. Inoculums were obtained from post-mortem human temporal cortex tissues by sucrose gradient fractionation. C57Bl/6J male mice were inoculated with Lewy Body (LB)-containing fractions (hsyn+) from patients with idiopathic PD; control-injected mice were inoculated with non-LB PD fractions (hsyn-), aggregated non-toxic fractions from non-PD patients (hCtrl), or the corresponding vehicle (Veh). Mice were evaluate

…Lewy bodies which consist mostly of alpha-synuclein. Astrocytes and microglia are increasingly being regarded as key players in PD-associated neurodegeneration, and these become ‘activated’ during neuroinflammation. Autophagy and its dysfunction have been implicated in some genetic forms of PD, with alpha-synuclein accumulation and aggregation linked to autophagy suppression. Using alpha-synuclein triplica

…PD-related pathology such as alpha-synuclein (aSyn) accumulation potentially affects the integrity of the BBB starting at an early disease stage. This could result in a self-perpetuating pathophysiology of inflammation and BBB alteration, which contributes to neurodegeneration.In our initial study, we described microvascular changes during disease progression in a mouse model with overexpression of human aSyn (Thy1-aSyn, l

…In the serotonin (5-HT) system alpha-synuclein (a-Syn) aggregates are present and functional changes are involved in the PD prodromal phase and contribute to non-motor symptoms​. Using a mouse model of depression and synucleinopathy in raphe 5-HT neurons, we aim to evaluate: 1- behavioral phenotype, 2- synaptic changes in prefrontal cortex and striatum, and 3- possible sex-based differences. METHODS: Recombinant adeno-associated viral vectors (AAV2/5) encoding wild-type human a-Syn (h-a-Syn) were infused in r

The traditional method in the development of drugs for neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, necessitates the use of various animal models to assess complex behavioral changes. This process is not only time-consuming but also prone to misjudgments due to interspecies behavioral differences. In contrast, neural activity data gathered by head-mounted microscopy platforms represent integrated information that is relatively straightforward to interpret and exhibits low variability between species. This makes it an excellent resource for the development of correspo

…and/or overexpressing corticostriatal alpha-synuclein may induce striatal astrocytosis in mice.Glutamatergic corticostriatal neurons in

Parkinson’s disease (PD) is usually thought of as a motor disorder, although non-motor symptoms may precede the motor manifestations and are a key component of the PD. Among these, depression and anxiety are most prevalent symptoms and caused a greater symptomatic burden in women than in men. A dysfunctional serotonin (5-HT) system is generally considered a risk factor for depression. We propose the ventromedial prefrontal cortex (vmPFC)-dorsal raphe nucleus (DR) circuit as the key player underlying depressive/anxious disorders in PD, by virtue of its reciprocal connectivity. Female mice overe

…emerges in the bilateral human mutated alpha-synuclein (A53T) rat model of PD.40 adult Sprague-

…aggregation, such as Beta-amyloid, Alpha-synuclein and Tau aggregation within synapses, remains limited. To address this, we present a novel method for visualizing protein aggregates in individual synaptosomes. We combined Single-molecule Pull Down (SiMPull) and direct Stochastic Optical Reconstruction Microscopy (dSTORM), to immobilize individual synaptosomes and characterize single aggregates within them with ~20nm spatial resolution

In this study, we aim to create a novel approach to understanding the complexity of alpha-synuclein (a-Syn) induced pathological changes at the cellular level in the ReNVM neural progenitor cells, that can readily differentiate into dopaminergic neurons. Additionally, we aim to analyze in greater detail intracellular changes and differences in extracellular signaling induced by a-Syn in a dosage-dependent manner.We created novel neuronal cell models of PD in ReNVM cells background, stably overexpressing GFP-tagged a-Syn either wild type (WT) or its A53T mutant via lentivirus transduction. Cell

Prodromal network hyperexcitability and mitochondrial dysfunction underly the pathogenesis of various forms of dementia. However, the role of hippocampal hyperexcitability and mitochondria in prodromal dementia with Lewy bodies (DLB) is unclear.We conducted multi-electrode array (MEA) recordings to investigate early hippocampal activity in a transgenic mouse model of DLB which harbours an alanine to proline point mutation (A30P) in the alpha synuclein gene (SNCA), causing overexpression. Hippocampal slices from young pre-symptomatic (2-4 months) male A30P (N = 6 slices/4 mice) and wild-type (W

…in Parkinson's disease(PD), where alpha-synuclein encoded by the SNCA gene has been observed to localize within the organelle as the disease progresses. Despite alpha-synuclein's significance in PD pathology, its specific roles within mitochondria still need to be better understood. In this study, we aimed to explore the impact of overexpression of the SNCA gene, which codes for the alpha-synuclein protein, on the expression of genes encoded by mitochondrial DNA (mtDNA).HEK-293T cells were transfected wi

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder and there is no cure to treat or prevent the disease. The cardinal motor symptoms of PD are caused by a decline of nerve cells producing the neurotransmitter dopamine, which is necessary for the initiation of voluntary movements, but other transmitter systems including the serotonin and norepinephrine systems are affected as well and are related to non-motor symptoms such as depression and dementia. On a pathological level, PD is also characterized by intracellular proteinaceous inclusions known as Lewy bodies that contain t

…of a pathogenic protein (alpha-synuclein) playing a key role in PD, a mouse model has recently been developed at Clinatec (CEA Grenoble) presenting chronic and progressive symptoms that aggravate over time. Neuroprotect

…mouse that expresses human mutant alpha-synuclein (hA30P). The study investigated whether there were early pre-symptomatic, neuroinflammatory changes in hA30P mice that could contribute to the network hyperexcitability previously observed.Studies were conducted using 1 month and 2-4 months old hA30P mice of both sexes and compared to age-matched wild-type (WT) mice. Fixed, frozen hippocamp

…where the most abundant protein is alpha-synuclein (a-SYN). In addition to the neurodegeneration and the accumulation of proteins, PD is characterized by chronic low-grade inflammation and mitochondrial alterations that lead to oxidative stress. Currently, the only treatment for PD patients is dopamine replacement therapy (levodopa), which has serious side effects and does

Parkinson’s disease (PD) is a neurodegenerative process characterized by the presence of Lewy bodies in different brain regions, affection of many neurotransmitter systems and manifestation of motor and nonmotor symptoms. These latter ones often appear before the motor symptomatology and highly impact on the life quality of the patients. Interestingly, the locus coeruleus (LC) that contains the highest density of noradrenergic neurons in the brain, is among the brain stem areas first displaying Lewy bodies in the disease, and is associated with prodromal non-motor symptoms. Despite its small s

…and where we produce region-specific alpha-synuclein path

Parkinson’s disease (PD) affects more than 6 million people worldwide, and will affect more in coming decades. There are no drugs available for PD that alter progression of disease. Current symptomatic treatments provide limited relief and have side effects. Enhanced GABAergic neurotransmission contributes to Parkinson’s disease (PD) pathogenesis and to some motor and non-motor symptoms. In animal models, GABA levels are increased in substantia nigra pars compacta, leading to reduced expression of tyrosine hydroxylase (TH) in neurons which contributes to the behavioural deficits. The aim was t

Parkinson’s disease (PD) is the second most common neurodegenerative disease with high burden on patients, but lack of disease modifying treatment. Therefore, identification of a cause for initiation and progression of this disease are research priorities. It is widely accepted, that the pathogenic aggregation of the alpha synuclein (aSyn) protein is involved in the loss of dopaminergic neurons in PD. In this project, we aim to illuminate the influence of hypoxia on the progression and initiation of PD in a murine model with focus on inflammation. Activity and differentiation of immune cells i