Abstract
The accumulation of proteinaceous deposits comprised largely of the α-synuclein protein is one of the main hallmarks of Parkinson's disease (PD) and related synucleinopathies. Their progressive development coincides with site-specific phosphorylation, oxidative stress and eventually, compromised neuronal function. However, modeling protein aggregate formation in animal or in vitro models has proven notably difficult. Here, we took advantage of a preclinical organotypic brain slice culture model to study α-synuclein aggregate formation ex vivo. We monitored the progressive and gradual changes induced by α-synuclein such as cellular toxicity, autophagy activation, mitochondrial dysfunction, cellular death as well as α-synuclein modification including site-specific phosphorylation. Our results demonstrate that organotypic brain slice cultures can be cultured for long periods of time and when cultured in the presence of aggregated α-synuclein, the molecular features of PD are recapitulated. Taken together, this ex vivo model allows for detailed modeling of the molecular features of PD, thus enabling studies on the cumulative effects of α-synuclein in a complex environment. This provides a platform to screen potential disease-modifying therapeutic candidates aimed at impeding α-synuclein aggregation and/or cellular transmission. Moreover, this model provides a robust replacement for in vivo studies that do not include behavioral experiments, thus providing a way to reduce the number of animals used in an accelerated timescale.
Highlights
Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder that affects ∼2 to 3% of individuals over the age of 65
The relationship between the progressive deposition of αsynuclein, motor dysfunction and cognitive decline have been highlighted for multiple α-synucleinopathies including PD and dementia with Lewy bodies [1,2,3]. α-synuclein is abundantly present in the central nervous system (CNS) where it is a critical mediator of synaptic vesicle trafficking [40]
Pathological structures that resemble in part, the hallmark Lewy bodies (LBs) and Lewy neurites (LNs) inclusions observed in the brains of postmortem PD patients [1,2,3, 7, 47,48,49,50]
Summary
Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder that affects ∼2 to 3% of individuals over the age of 65. The main neuropathological hallmarks of this disease are the formation of Lewy bodies (LBs) and Lewy neurites (LNs), intracellular inclusions consisting mainly of α-synuclein aggregates, which are predominantly located in the substantia nigra pars compacta (SNpc) and other vulnerable brain regions [1,2,3]. Subsequent neuronal loss and dopamine deficiency cause progressive motor deficits observed in PD patients [4, 5]. An Organotypic Slice Culture Model for PD of α-synuclein in vulnerable brain regions may be responsible for PD pathogenesis [8]. The cause of these detrimental events likely involves dysfunction of multiple cellular pathways responsible for proteostasis, cellular trafficking, and the proper function of mitochondria, axons, and synapses [2, 8]
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