Parkinson’s disease

Investigate and validate therapeutic targets for Parkinson’s disease through neuronal and glial models, including iPSC-derived cells and co-cultures. Design cellular and biochemical experiments to clarify mechanisms of action and translate findings into drug-discovery decisions. The advertised salary range is USD 143,000–173,250. The exact role page currently accepts applications and does not state a fixed closing date.

Study cellular mechanisms of Parkinson’s disease in the Jan Lab. Research integrates patient genetics, genomics and biomarkers with cellular and animal models, functional-genomic screening and measurements of morphology and transcription. Fellows develop independent projects during a three-year programme with a possible fourth year.

…to disorders such as Parkinson's disease and autism. The Research Technician conducts behavioral assays and data processing, performs surgical manipulations and tissue collection under lab protocols, carries out histology (vibratome sectioning, immunohistochemistry, slide imaging), assists with bird colony care and supports ge

The ability to recognize and interpret shifts in naturalistic behavioral expression across neural (dys)function is critical to systems neuroscience study. Recent developments in computer vision have enabled continuous measurements of 3D keypoints on freely moving animals. Common analysis objectives seek to cluster these time series into recurring and stereotyped behaviors (e.g., running or rearing) and compare their frequencies across experimental conditions. Currently, most behavioral analysis approaches are purely unsupervised and can be sensitive to nuisance variability, such as an animal's

…of dopaminergic drive in Parkinson's disease manifests in deficits of movement timing and initiation. While the role of dopamine in the cortex-basal ganglia-thalamaus (C-BG-T) loop has been explored within the framework of reinforcement learning, computational models of how dopamine might influence fast-timescale movement generation have not been explored to the same extent. Here, we propose

Parkinson’s disease (PD) has been associated with alterations in neuronal activity in the basal ganglia-thalamocortical network. The motor cortex (M1) is a key node in this network and likely plays a significant role in the expression of impaired movement in PD. Altered neuronal activity in M1 has been reported and characterized at the single-unit level in PD, however, results are difficult to reconcile under one theoretical model (Doudet et al., 1990; Watts \& Mandir, 1992; Pasquereau et al., 2016). One promising avenue toward a mechanistic understanding of M1 pathophysiology in PD is to inve

Parkinson's disease (PD), characterized by the absence of dopamine in the striatum[1], is caused by the death of the substantia nigra pars compacta dopamine (SNcDA) neurons in the midbrain. The loss of these autonomously pacemaking[2] neurons is attributed to irreparable damage due to a dysregulation cascade starting from excess cytosolic dopamine and its decomposition into its aldehyde[3]. However, it is unresolved if dopamine dysregulation in SNcDA neurons themselves is the cause of PD or if it is a mere symptom. Here, we applied a recent theory of metabolic spikes[4] to SNcDA neurons, to

…In the specific case of Parkinson's disease (PD), the brain loses dopaminergic neurons in the substantia nigra compacta (SNc). Highly involved in the basal ganglia-cortex-thalamus-cerebellum (BG-Ctx-T-Cb) network, the main role of dopamine (DA) is in learning, decision-making and motor control, as manifested in the PD symptoms such as rigidity, slowness of movements, tremor and poor behavioural flexibility. Following DA loss, the un

The major neuropathologic feature of Parkinson’s disease is the presence of widespread intracellular inclusions of α-synuclein known as Lewy bodies. Evidence suggests that these misfolded protein inclusions spread through the brain with disease progression. Changes in synaptic function precede neurodegeneration, and this extracellular α-synuclein can affect synaptic transmission. However, whether and how the spreading of α-synuclein aggregates modulates synaptic function before neuronal loss remains unknown. In the present study, we investigated the effect of intrastriatal injection of α-synuc

Parkinson’s disease (PD) results in midbrain dopaminergic neuron degeneration 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

Synapse degeneration contributes to cognitive decline in neurodegenerative diseases. We have previously demonstrated 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

Achyrocline satureoides aqueous extract (ASAE) protective effects were evaluated on dopaminergic neurodegeneration induced by reserpine in Caenorhabditis elegans (C. elegans). Strain BY200 was cultured following standard procedure. The worms (L1 stage) were exposed to the treatments, ASAE (10 or 25 mg/ml) or no for 24 hours, followed by the induction of dopaminergic damage (reserpine, 60 µM, positive control; PC) or no (negative control; NC). Worm’s images (n=20) were captured using a fluorescence microscope and quantified using the ImageJ software. The locomotor behavior (body bends) of the w

Adenosine Deaminases Acting on RNA (ADAR) enzymes catalyse the conversion of adenosine (A) to inosine (I) within double-stranded RNA (dsRNA) molecules. This mechanism, known as A-I RNA editing, is able to modulate gene expression, RNA stability and protein function.Recently, new therapeutic approaches based on site-directed RNA editing (SDRE) leverage the recoding ability of ADAR to correct pathogenic G to A nucleotide mutations. SDRE allows for the manipulation of genetic information without causing damage to the genome. G-to-A point mutations make up nearly 30% of the pathogenic single nucle

…of neurodegeneration, in particular of Parkinson’s Disease (PD). Clinical research is currently challenging the assumption that human sleep is a one-fits-all phenomenon: breaking new grounds into sleep research is needed. In this scenario, the European Research Council PathFinder Open project NAP proposes a new science-toward-technology paradigm enabling the study of hu

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

Parkinson's disease is a motor and cognitive neurodegenerative disorder associated to the progressive loss of Substantia Nigra pars compacta dopaminergic neurons. One cause of the disease is associated with the spreading of α-synuclein aggregates. Recent findings indicate that extracellular α-synuclein oligomers represent the most neurotoxic species and reduce the firing discharge of midbrain neurons, impair network synchronization, up-regulate Cav2.2 Ca channels and neurotransmitter release in cortical neurons. Here we combined conventional electrophysiology (current-clamp) and diamond multi

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra, and it has been reported that α-synuclein accumulates in the gut and then affects the brain along the gut-brain axis. In this study, we used Enterococcus faecium (EF), which was probiotics, that confer health benefits on the host when administered in adequate amounts. C57BL/6 mice, a model of PD induced by MPTP, were treated with EF (1ⅹ1012 CFU/mL). The study showed that motor dysfunction in MPTP-induced PD model mice improved. Additionally, EF was found to decrease the accumulation o

Previous studies provided that Aβ1-42 peptide, a pathological component of Alzheimer's disease (AD), and α-synuclein, the major protein of Lewy bodies in Parkinson's disease (PD), may interact with transcription factors and affect gene transcription. Researchers have revealed that Aβ1-42 can be found in the nucleus, interact with DNA, and change the expression of many genes. It is known that α-synuclein functions as a transcription factor that binds to nuclear DNA and modulates the expression of many genes. Our study aims to investigate whether these peptides directly affect the expression of

Parkinson’s disease (PD) represents one of the most frequent neurodegenerative disorders for which genetic diagnosis is still challenging. We have recently reported the identification of rare new gene variants in PD patients that support polygenic contribution to the disease. Here we report the identification of novel PD genes and a novel protocol for predictive analysis of PD risk.The study includes the whole exome data of 22 PD families, 804 unrelated PD and 282 healthy subjects.Family-based approach identified rare and disrupting variants, in 44 candidate genes, co-inherited by affected rel

Among symptoms characterizing Parkinson’s disease (PD), freezing of gait (FoG) can become particularly disabling for patients. Anxiety levels have been linked to the severity of FoG, yet in this circumstance, levodopa treatment lacks effectiveness. A better understanding of the neural circuit mechanisms underlying FoG is required for a more targeted approach towards its treatment. To this end, we developed a viral vector (AAV2/9-CreON-A53T-αSyn) mouse model restricting synucleinopathy to local circuit elements, i.e. selected neuron subtypes within specific brain regions in vivo. We validated t

…exponent is sensitive to levodopa in Parkinson’s disease, but there is no clear evidence of its relationship to PD motor symptoms. This study aims to explore the correlation between the aperiodic exponent of subthalamic nucleus activity and rigidity and bradykinesia.Fourteen PD patients underwent bilateral STN DBS surgery with temporary leads externalization. LFPs were recorded in OFF and ON states several days a

Promising alternative strategies, such as repurposing drugs, have been considered for Parkinson’s Disease (PD). Within this framework, N-acetylcysteine (NAC) has shown promising results in preserving the dopaminergic system. Indeed, published data from our group revealed that NAC single-dose administration enhanced DAn viability, as we found that it could restore dopamine transporter (DAT) levels. With this in mind, we consider that NAC application could be a remarkable asset to approach PD. Therefore, in the present study, we addressed the impact of a 7-day treatment with NAC in a 6-hydroxydo

Parkinson’s disease (PD) is a neurodegenerative disorder that is mainly characterised by the loss of dopaminergic neurons in the substantia nigra as well as the presence of aggregates called 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

Parkinson's disease (PD) is a neurodegenerative disease primarily characterized by severe motor symptoms that can be transiently relieved by medication (levodopa). While there is evidence of widespread alterations of the neuronal activities across the brain, reliable biomarkers are still lacking. To examine this question, we measured the resting state activities of 11 PD patients both with deep stimulation electrodes and with EEG electrodes placed in the motor areas, in order to provide simultaneous recording from both the subthalamic nucleus (STN) and the cortex. Then, we used a dynamical mea