In vivo models of alpha-synuclein transmission and propagation

Abstract

The abnormal accumulation of α-synuclein aggregates in neurons, nerve fibers, or glial cells is the hallmark of a group of neurodegenerative diseases known collectively as α-synucleinopathies. Clinical, neuropathological, and experimental evidence strongly suggests that α-synuclein plays a role not only as a trigger of pathological processes at disease inception, but also as a mediator of pathological spreading during disease progression. Specific properties of α-synuclein, such as its ability to pass from one neuron to another, its tendency to aggregate, and its potential to generate self-propagating species, have been described and elucidated in animal models and may contribute to the relentless exacerbation of Parkinson's disease pathology in patients. Animal models used for studying α-synuclein accumulation, aggregation, and propagation are mostly based on three approaches: (1) intra-parenchymal inoculations of exogenous α-synuclein (e.g., synthetic α-synuclein fibrils), (2) transgenic mice, and (3) animals (mice or rats) in which α-synuclein overexpression is induced by viral vector injections. Whereas pathological α-synuclein changes are consistently observed in these models, important differences are also found. In particular, pronounced pathology in transgenic mice and viral vector-injected animals does not appear to involve self-propagating α-synuclein species. A critical discussion of these models reveals their strengths and limitations and provides the basis for recommendations concerning their use for future investigations.

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

“…Unfortunately, these models do not recapitulate the α‐syn aggregation observed clinically in PD patients . In this case, we have the following different options: (1) intraparenchymal inoculations of exogenous α‐syn (eg, synthetic α‐syn fibrils), (2) transgenic mice, and (3) animals in which α‐syn overexpression is induced by viral vector injections …”

Sensing α‐Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration

“…A requirement for the “prion‐like” spreading is the transfer of αSyn between cells. Different mechanisms have been hypothesized to be involved in this process (Fig. ).…”

Special issue “Parkinson’s disease”

“…Although multiple lines of evidence support the hypothesis of the self-propagating (prion-like) spread of aggregates as a major pathogenic mechanism in Lewy body disorders, it is important to point out that this may not reflect the entire story, as some in vivo models, including those using viral vectormediated overexpression of α-synuclein to induce pathology, do not appear to involve this process, as discussed by Recasens et al (2018). Does human-derived α-synuclein possess the same pathogenic properties observed in synthetic recombinant α-synuclein aggregates (Osterberg et al 2015) and in rodent-derived forms?…”

“…Four additional articles in this special volume focus on the mechanisms of intercellular spreading by α-synuclein aggregates in what often is termed a "prion-like" manner (Grozdanov and Danzer 2018;Recasens et al 2018;Peelaerts et al 2018;Tamgüney and Korczyn 2018). Nerve cells possess three strategies for dealing with abnormal proteins, including α-synuclein: degradation and elimination, inclusion body formation (protein deposition), or release into the extracellular space (Grozdanov and Danzer 2018).…”