Synuclein

Addressing C-F bonds and amyloid-formation in biological systems

The ingestion, pulmonary inhalation, and dermal infiltration of C-F bond-containing compounds, most commonly found in the form of per- and polyfluoroalkyl organic acids, causes oxidative stress, inflammation, DNA damage, and developmental defects in infants and adults. These chemicals accumulate in the brain, disrupt neurological function and compromise cognitive and locomotory behavior. Yet, we lack a high-resolution road-map of the interactions between C-F bonds and biomolecular assemblies driving the trajectory towards neurodegenerative outcomes. This gap constitutes a significant barrier to advancing measures designed to mitigate C-F chemistry-associated neurotoxicity. Emerging experimental and computational data from our laboratory reveals that perfluorooctanoic acid, perfluorodecanoic acid and perfluorosulfonic acid corrupt biomolecular structures through C-F:side-chain interactions in tested soluble, globular proteins found in milk and tissues (matrices where C-F chemistries have been detected). Furthermore, they impaired the physiological function in these proteins through displacement of physiological ligands or by compromising the binding of co-factors. The neuroblastoma-derived SHSY-5Y cell line insulted with the said C-F moieties displayed altered gene expression corresponding to reactive oxygen species (ROS), protein ubiquitination, inflammation along with compromised cytoskeletal integrity. C-F bond ingestion ablated dopaminergic (DA) neurons in the nematode C. elegans and induced locomotory deficits in a manner mimicking paraquat. Based on these findings, we propose to gather data towards our hypothesis that C-F bond exposure perturbs biomolecular, cellular and organismal assemblies to onset neurodegeneration-linked trajectories. In Aim 1, we will determine whether organic fluoroacids alter mRNA levels in differentiated SHSY-5Y cells and in neuroprotective gut bacteria (Lactobacillus rhamnosus, Bifidobacterium lactis and Lactobacillus acidophilus). We will examine whether the neuroblastoma cell line exposed to C-F chemistry displays readouts designed to inform the onset of neurodegeneration-associated trajectories (including α-synuclein aggregation). In Aim 2, we will further address in a preclinical model whether C-F burden induces protein aggregation (α-synuclein, amyloid β, mHTT), interferes with dopaminergic neuronal assembles and induces locomotory deficits. Completion of the proposed work will complement ongoing experimental biophysical, structural (crystallographic, NMR) and computational (docking, molecular dynamics simulations) mapping of the interactions between these anthropogenic “forever” chemicals and amyloid-forming proteins potentially resulting in a soluble-to-toxic transformation. It will prepare the stage for vertebrate testing. The findings from this relatively understudied area likely exposes interventional targets for C-F chemistry associated neurotoxicity, spurs therapeutic efforts and can also guide the development of more biocompatible alternatives.

The synaptic functions of Alpha Synuclein and Lrrk2

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.

Alpha synuclein in parkinson's Disease: From the bedside to the bench and back again

Multimodal imaging in Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a synucleinopathy but more than half of patients with DLB also have varying degrees of tau and amyloid-β co-pathology. Identifying and tracking the pathologic heterogeneity of DLB with multi-modal biomarkers is critical for the design of clinical trials that target each pathology early in the disease at a time when prevention or delaying the transition to dementia is possible. Furthermore, longitudinal evaluation of multi-modal biomarkers contributes to our understanding of the type and extent of the pathologic progression and serves to characterize the temporal emergence of the associated phenotypic expression. This talk will focus on the utility of multi-modal imaging in DLB.

Multimorbidity in the ageing human brain: lessons from neuropathological assessment

Age-associated dementias are neuropathologically characterized by the identification of hallmark intracellular and extracellular deposition of proteins, i.e., hyperphosphorylated-tau, amyloid-β, and α-synuclein, or cerebrovascular lesions. The neuropathological assessment and staging of these pathologies allows for a diagnosis of a distinct disease, e.g., amyloid-β plaques and hyperphosphorylated tau pathology in Alzheimer's disease. Neuropathological assessment in large scale cohorts, such as the UK’s Brains for Dementia Research (BDR) programme, has made it increasingly clear that the ageing brain is characterized by the presence of multiple age-associated pathologies rather than just the ‘pure’ hallmark lesion as commonly perceived. These additional pathologies can range from low/intermediate levels, that are assumed to have little if any clinical significance, to a full-blown mixed disease where there is the presence of two distinct diseases. In our recent paper (McAleese et al. 2021 Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia, https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12291, Alzheimer's & Dementia), using the BDR cohort, we investigated the frequency of multimorbidity and specifically investigated the impact of additional low-level pathology on cognition. In this study, of 670 donated post-mortem brains, we found that almost 70% of cases exhibited multimorbidity and only 22% were considered a pure diagnosis. Importantly, no case of Lewy Body dementia or vascular dementia was considered pure. A key finding is that the presence of low levels of additional pathology increased the likelihood of having mild dementia vs mild cognitive impairment by almost 20-fold, indicating low levels of additional pathology do impact the clinical progression of a distinct disease. Given the high prevalence and the potential clinical impact, cerebral multimorbidity should be at the forefront of consideration in dementia research.

Targeting selective autophagy against neurodegenerative diseases

Protein quality control is essential for maintenance of a healthy and functional proteome that can attend the multiplicity of cellular functions. Failure of the systems that contribute to protein homeostasis, the so called proteostasis networks, have been identified in the pathogenesis of multiple neurodegenerative disorders and demonstrated to contribute to disease onset and progression. We are interested in autophagy, one of the components of the proteostasis network, and in the interplay of wo selective types of autophagy, chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI), with neurodegeneration. We have recently found that pathogenic proteins involved in common neurodegenerative conditions such as tauopathies or Parkinson’s disease, can exert a toxic effect in both types of selective types of autophagy compromising their functioning. We have now used mouse models with compromised CMA that support increased propagation of proteins such as tau and alpha-synuclein and an exacerbation of disease phenotype with aging. Conversely, genetic or chemical upregulation of CMA in this context of proteotoxicity slow down disease progression by facilitating effective intracellular removal of pathogenic proteins. Our findings highlight CMA and eMI as potential novel therapeutic targets against neurodegeneration.

Neurotoxicity is a major health problem in Africa: focus on Parkinson's / Parkinsonism

Parkinson's disease (PD) is the second most present neurodegenerative disease in the world after Alzheimer's. It is due to the progressive and irreversible loss of dopaminergic neurons of the substantia nigra Pars Compacta. Alpha synuclein deposits and the appearance of Lewi bodies are systematically associated with it. PD is characterized by four cardinal motor symptoms: bradykinesia / akinesia, rigidity, postural instability and tremors at rest. These symptoms appear when 80% of the dopaminergic endings disappear in the striatum. According to Braak's theory, non-motor symptoms appear much earlier and this is particularly the case with anxiety, depression, anhedonia, and sleep disturbances. In 90 to 95% of cases, the causes of the appearance of the disease remain unknown, but polluting toxic molecules are incriminated more and more. In Africa, neurodegenerative diseases of the Parkinson's type are increasingly present and a parallel seems to exist between the increase in cases and the presence of toxic and polluting products such as metals. My Web conference will focus on this aspect, i.e. present experimental arguments which reinforce the hypothesis of the incrimination of these pollutants in the incidence of Parkinson's disease and / or Parkinsonism. Among the lines of research that we have developed in my laboratory in Rabat, Morocco, I have chosen this one knowing that many of our PhD students and IBRO Alumni are working or trying to develop scientific research on neurotoxicity in correlation with pathologies of the brain.

Altered polyunsaturated sphingolipids correlate with α-synuclein in Multiple System Atrophy Cerebellar subtype

Assessment of repetitive and compulsive behaviours induced by pramipexole in rats: effect of alpha-synuclein-induced nigrostriatal degeneration

Blaming neuromelanin for Parkinson's disease: time-dependent tyrosinase overexpression drives endogenous synucleinopathy in nonhuman primates

Characterization of a novel Glucocerebrosidase pharmacological chaperone in vitro and in vivo models of alpha synuclein neurotoxicity

Cultured mouse dopaminergic neurons as a model system to study alpha-Synuclein aggregation and neurodegeneration in Parkinson’s disease

Sex differences in behavioral phenotype and markers of the unfolded protein response (UPR) pathway in a mouse model overexpressing human α-synuclein

The effects of alpha-Synuclein on the phase separation at synapses

Effects of inflammation in the progression of Parkinson’s Disease in a rat model overexpressing human α-synuclein

Encapsulated-cell bio-delivery of prosaposin counteracts AAV-α-synuclein-induced parkinsonism

Evidence for prodromal neuroinflammation in a rodent model of alpha- synucleinopathy

Extracellular Clusterin prevents alpha-synuclein dispersion

Glucocorticoid receptors in astrocytes regulate alpha-synuclein pathological actions impacting motor and non-motor symptomology of Parkinson’s disease

Glycation of alpha-synuclein modulates aggregation and Parkinson’s disease-like phenotypes

Host to graft propagation of alpha-synuclein in Parkinson’s disease: intra-nigral versus intra-striatal transplantation

Identifying alpha-synuclein interactome map in a mouse model using proximity-biotinilation

Influence of the apolipoprotein e4 allele (ApoE4) on astrocytic and neuronal acetylation landscapes in physiological and α-synuclein-induced pathological contexts

The Interplay of Lipopolysaccharide and Alpha-Synuclein to Model Gut-Brain Pathophysiology in Parkinson´s Disease

Loss of GBA activity exacerbate the toxicity of alpha-synuclein oligomers and protofibrils in an in vitro model of Parkinson’s disease

Modelling presymptomatic stages of Parkinson’s disease in rodents by the overexpression of human alpha-synuclein in the locus coeruleus

Morphological and functional changes of nigral dopamine neurons in an α-synuclein overexpressing rat model of Parkinson’s disease

Neuronal hemoglobin induces loss of dopaminergic neurons in mouse Substantia nigra, cognitive deficits and cleavage of endogenous α-synuclein

Neurotoxic effects of beta-Synuclein and its mutants, P123H and V70M

Priming mesenchymal stem cells with α-synuclein enhances neuroprotective properties through induction of autophagy in Parkinsonian models

Rabphilin-3A as novel target to rescue alpha-synuclein induced synaptic loss in Parkinson’s disease

Reduced Interaction of Aggregated α-Synuclein and VAMP2 by Environmental Enrichment Alleviates Hyperactivity and Anxiety in a Model of Parkinson’s Disease

The role of activity-dependent phosphorylation in the presynaptic function of α-synuclein

The role of EEF1A proteins at synapses and in synucleinopathy

The role of microvascular changes during development and progression of Parkinson’s Disease in a human alpha-synuclein overexpression mouse model (line 61)

Role of TGF-beta signalling pathway against alpha synuclein-induced toxicity in a Parkinson’s disease cell model

Saposin C reduces levels of α-synuclein and dislodges it from glucosylceramide-enriched lipid membranes

Studying mitophagy in neuronal models of alpha-synucleinopathy with the fluorescent MitoRosella reporter

Super-resolving alpha-synuclein transmission: from exosomal release to downregulation of axonal retrograde transport flux in recipient neurons

Time-course of motor behavioural, neurodegenerative and neuroinflammatory changes after viral vector-mediated overexpression of alpha-synuclein in the mouse substantia nigra

Understanding the behavioural and morphological changes in an alpha-synuclein rat model of Parkinson´s disease

Uric acid regulates neuron-to neuron α-synuclein transmission in Parkinsonian microenvironment

Using viral vectors to study the synergistic developmental effects of tau, alpha-synuclein and amyloid-beta

New in vivo model of Parkinson’s disease involving combined toxicity of alpha-synuclein oligomers and protofibrils, and chronic inhibition of GBA

α-Synuclein propagation leads to synaptic abnormalities in the cortex through microglial synapse phagocytosis

FENS Forum 2024

AAV-mediated overexpression of wild-type human alpha-synuclein leads to alterations in gut microbiota in a ‘brain-first’ rat model of prodromal Parkinson’s disease

FENS Forum 2024

Ablation of carotid body activity prevents cognitive dysfunction and decreases alpha-synuclein levels in the brain of an animal model of dysmetabolism