Organotypic hippocampal slices, an emerging tool to model synucleinopathies.

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Date: May 2021
From: Neural Regeneration Research(Vol. 16, Issue 5)
Publisher: Medknow Publications and Media Pvt. Ltd.
Document Type: Article
Length: 2,371 words
Lexile Measure: 1580L

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Byline: Sara. Elfarrash, Poul. Jensen

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. PD has been traditionally considered a motoric disorder characterized by tremor, rigidity and bradykinesia, however it is now settled that PD also comprises a range of non-motor symptoms like hyposmia, sleep disturbances and cognitive impairments (Tysnes and Storstein, 2017).

The pathological hallmark of PD is the presence of neuronal cytoplasmic inclusions called Lewy bodies (LB) or Lewy neurites, which consist of the abundant presynaptic protein alpha-synuclein (a-syn) in an aggregated form. Apart from being present in all LB, a-syn is causally involved in rare cases of PD, where a-syn encoding SNCA gene either contains missense mutations or is dupli- or triplicated causing autosomal dominant familiar PD. Moreover, SNCA gene polymorphism is now believed to be a significant risk factor for the development of sporadic PD (Henderson et al., 2019).

Under normal condition, a-syn exists as native soluble form, but in PD, a-syn aggregates and accumulates as soluble oligomers and insoluble filaments in the diseased neurons. This process is governed by different factors related to ageing, genetics and environmental pollutants (Henderson et al., 2019).

Braak et al. (2003) formulated a hypothesis that suggests the spreading of a-syn aggregate pathology to and within the nervous system. Braak et al. (2003) proposed that the initial Lewy pathology starts at olfactory bulb or in the gut and then spreads to brain stem via vagal nerve, and this finding had been corroborated later by a large body of clinical and experimental evidences (Braak et al., 2003; Li et al., 2008, 2010).

In vitro studies have demonstrated that inoculation of recombinant preformed fibrils of a-syn (PFFs) or brain homogenates containing a-syn aggregates into the brains or peripheral tissue of animal models can initiate a progressive process of aggregation of endogenous a-syn. These newly formed aggregates are capable to spread between connected neurons triggering neuronal dysfunction and cell death. The biochemical and histopathological analysis of induced aggregates replicate the criteria of LB, namely ubiquitination and hyper phosphorylation (Delenclos et al., 2019).

Mechanistically, the available data support that a-syn aggregates, so-called seeds, are excreted from affected neurons and taken up by a neighboring healthy neuron where they template the aggregation of its native a-syn in a prion-like style. Hereafter, the process can replicate and spread further through the tissue. Evidences support that Braak's hypothesis is also applicable to other a-syn related diseases -collectively called synucleinopathies, e.g., dementia with LB and multiple system atrophy in different cellular and animal models in an anterograde or retrograde manner (Henderson et al., 2019). Furthermore, a recent in vivo study demonstrated that spreading of PFFs induced a-syn aggregates pathology can occur in both a retro- and anterograde manner upon inoculation of the seeds in the gut, replicating pathology observed in PD (Van Den Berge et al., 2019). So, to fully understand the mechanism of a-syn pathology spreading and progression, further investigations that reveal the molecular mechanisms of a-syn seeding, secretion, and how they are subsequently...

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Gale Document Number: GALE|A642710652