Synuclein
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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
Synuclein coverage
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