Relationship between α-synuclein aggregate accumulation and aquaporin-4 expression in multiple system atrophy and Dementia with Lewy Bodies

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Pountney, Dean L
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Ralph, Stephen J
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2024-02-26
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Abstract

Multiple system atrophy (MSA) and Dementia with Lewy Bodies (DLB) are atypical Parkinsonian disorders or synucleinopathies characterised by accumulation of alphasynuclein (α-synuclein) protein deposits in the form of Lewy bodies (LB), Lewy neurites (LN) and glial cytoplasmic inclusions (GCI). Accumulation of these protein aggregates are responsible for the loss of dopaminergic neurons in the substantia nigra (SN) and subsequent motor deficits and non-motor symptomology, such as dementia in the case of DLB. Mounting evidence suggests that protein aggregates can alter the perivascular expression of astrocytic aquaporin-4 (AQP4), thus disrupting glymphatic flow and waste clearance. The glymphatic system is a brain-wide network of perivascular channels that preserves brain homeostasis by facilitating fluid exchange and clearance of cellular waste. The perivascular expression of astrocytic AQP4 has been identified as a key component of the glymphatic network, functioning as a water-selective transporter that regulates glymphatic flow. Efficient glymphatic flow ensures the timely removal of neurotoxic substances such as a-synuclein from the brain's interstitial space. If the glymphatic system is compromised, as may occur with impaired expression of aquaporin-4, the clearance of α-synuclein is impeded. The accumulation of α-synuclein aggregates triggers an inflammatory response, further exacerbating neuronal damage. Consequently, impaired waste clearance not only allows for the build-up of detrimental protein aggregates but also fosters a neuroinflammatory environment, both of which are implicated in the progression of MSA and DLB. Understanding and addressing the role of glymphatic flow in clearing α-synuclein may provide insights into potential therapeutic strategies for mitigating the impact of Parkinson's and related neurodegenerative disorders. [...]

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Thesis (Masters)
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Master of Medical Research (MMedRes)
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School of Pharmacy & Med Sci
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glymphatic system
aquaporin
Parkinson's Disease
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