Browsing by Subject "alpha-synuclein"

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    Investigating the mechanisms underlying synaptic and cognitive deficits in alpha-synucleinopathies
    (2019-06) Singh, Balvindar
    Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically related -synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. While alpha-synuclein (aS) abnormalities are directly implicated in PDD and DLB pathogenesis, it is unknown how aS contributes to memory loss. Previously, we found that familial Parkinson’s disease (PD)-linked human mutant A53T aS causes aberrant mislocalization of tau to dendritic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the progressive postsynaptic and memory deficits observed in a mouse model of alpha-synucleinopathy (TgA53T) are mediated by tau. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau-/-) completely ameliorates cognitive dysfunction and concurrent synaptic deficits. Memory deficits in TgA53T mice were also associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau-/- mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results implicate tau as a mediator of human mutant A53T aS-mediated abnormalities and suggest a mechanism for memory impairment that occurs via synaptic dysfunction rather than synaptic or neuronal loss. Fibrillar species of aS have also recently been implicated as a pathogenic component of synucleinopathies, capable of transmission between neurons and brain regions including the hippocampus. However, how aS fibrils impact hippocampal function and contribute to memory deficits are not well understood. We hypothesized that aS fibril-induced synaptic changes could be mediated through interactions with other proteins, including tau. Primary hippocampal neurons acutely exposed to fibrillar aS species display tau missorting to dendritic spines and both pre and postsynaptic electrophysiological deficits. However, some of these findings may be a product of concentration-dependent fibril-induced spine collapse. Importantly, the pathways behind fibril-mediated tau missorting and synapse loss could be differentiated in vitro. Taken together, these studies suggest that pathological aS fibrils and aggregates may act through distinct intracellular and extracellular mechanisms to contribute to neuronal dysfunction and neuronal toxicity. These approaches and results collectively indicate that pathological mutant and aggregated species of aS can drive synaptic deficits and represent potential therapeutic targets for amelioration of memory deficits in alpha-synucleinopathies.
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    Microglial morphology as a factor of sex and SNCA gene status
    (2022) Boes, Samuel A; Kim, Minwoo; Brown, Jennifer L; Lesné, Sylvain E
    Microglia comprise the immune system of the central nervous system. Microglia vary in morphology and in transcriptional and translational profiles. These factors are indicative of function and activation state. The role of the protein alpha-synuclein in neurons is established but remains unclear in microglia. Austin et al. (2006) found that cultured SNCA-knockout microglia display morphologically and translationally distinct profiles as compared to cultured wildtype neurons, but little work has been done to characterize microglial morphology in SNCA-knockout and wildtype mice in vivo. Because Brown et al. (unpublished) found changes in the expression of several genes associated with microglial activation in the hippocampi of SNCA-knockout mice compared to wildtype, the aim of this work was to determine the morphology of microglia in the CA1 of SNCA-knockout and wild-type mice. Confocal microscopy was used to capture high magnification and high resolution images of single microglia from SNCA-knockout and wildtype mice of both sexes (n = 40). Cell morphology was then characterized using Imaris Filament Tracer. SNCA-knockout exhibits a sex-dependent effect on microglial morphology. Microglia from SNCA-knockout female possess significantly more segments, branch points, and terminal points than do cells from wildtype females. These results are suggestive of a hypersurveillant microglial phenotype in SNCA-knockout females. More studies are warranted that compare the phagocytic activity and response to inflammation of microglia in SNCA-knockout and wildtype mice.