Early fine motor impairment and behavioral dysfunction in (Thy‐1)‐h[A30P] alpha‐synuclein mice

Ekmark‐Lewén, Sara; Lindström, Veronica; Gumucio, Astrid; Ihse, Elisabeth; Behere, Anish; Kahle, Philipp J.; Nordström, Erik; Eriksson, Marcus; Erlandsson, Anna; Bergström, Joakim; Ingelsson, Martin

doi:10.1002/brb3.915

Cited by 27 publications

(51 citation statements)

References 51 publications

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“…We propose that neurons with chronic overexpression of human A30P aSyn can still maintain retrograde transport and collect aSyn aggregates in perinuclear accumulations (SAs). Indeed, in the A30P mice without PFF injection, basal aSyn pathology is mostly restricted to somatic accumulations (SAs, reminiscent of LBs) with only few dystrophic neurites (DNs, reminiscent of LNs), consistent with earlier studies [22]. These mice do not show a loss of dopaminergic somata in the substantia nigra, degeneration of dopaminergic axon terminals in the striatum or glial activation (Figs.…”

Section: Discussionsupporting

confidence: 89%

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Targeting the N-terminus of α-synuclein Monomer Reduces Fibril-induced Aggregation in the Brain

Szegő¹,

Boß²,

Komnig³

et al. 2020

Preprint

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Background Removing α-synuclein aggregates or preventing their formation constitutes a plausible strategy against Parkinson’s disease (PD). As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein (aSyn), interferes with fibril nucleation and reduces aSyn aggregates in vitro and in a fruit fly model of A53T aSyn toxicity. Here we tested whether AS69 could also reduce aSyn pathology in mammalian neurons and in mouse brain. Methods Primary mouse neurons were exposed to pre-formed fibrils (PFF) of human WT aSyn or PFF was injected into the striatum of A30P-aSyn transgenic mice to induce aSyn pathology. Densities of phospho-aSyn positive somatic inclusions and dystrophic neurites, degeneration of dopaminergic axon terminals in the striatum and the glial response were determined. Results PFF were readily taken up by primary mouse neurons, and AS69 did not alter PFF uptake. aSyn pathology, as determined by phospho-aSyn staining, was much more pronounced 72 h after PFF addition than after 24 h, and was reduced by AS69. In the striatum, PFF increased aSyn pathology, induced degeneration of dopaminergic axon terminals and glial activation at 90 days after PFF injection. The extent of terminal loss correlated with the density of dystrophic neurites, but not with the number of somatic inclusions. Co-injection of AS69 with PFF abrogated the induction of somatic inclusions and dystrophic neurites, reduced the loss of dopaminergic axon terminals and the reaction of astroglia, but not the effect on microglia. Conclusion AS69, an aSyn monomer-binding protein, reduces aSyn pathology and loss of dopaminergic terminals in primary neurons and in a mouse model. Therefore, our data suggests, that small aSyn-monomer binding proteins, such as AS69, could be promising new therapeutic approaches against Parkinson's disease.

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Section: Discussionsupporting

confidence: 89%

“…These mice do not show a loss of dopaminergic somata in the substantia nigra, degeneration of dopaminergic axon terminals in the striatum or glial activation (Figs. 2B, 3A and reference [11]), but their neurons are vulnerable [13,[22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Targeting the N-terminus of α-synuclein Monomer Reduces Fibril-induced Aggregation in the Brain

Szegő¹,

Boß²,

Komnig³

et al. 2020

Preprint

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“…The MCSF has since its conception over a decade ago, proven useful in a number of studies using adult rats (Karlsson et al, 2009; Roman et al, 2012; Momeni and Roman, 2014; Palm et al, 2014; Magara et al, 2015) and mice (Augustsson and Meyerson, 2004; Ekmark-Lewén et al, 2010; Ekmark-Lewén et al, 2018). More recently, studies examining adolescent rats (Palm et al, 2013; Berardo et al, 2016; Wille-Bille et al, 2017, 2018) and mice (Stringer et al, 2017) have started using the MCSF as well.…”

Section: Discussionmentioning

confidence: 99%

Adolescent Exploratory Strategies and Behavioral Types in the Multivariate Concentric Square FieldTM Test

Lundberg

Högman

Roman

2019

Front. Behav. Neurosci.

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Adolescence is an important developmental phase with extensive changes in behavior due to remodeling of the brain and hormonal systems. Validation of animal behavioral tests in this age group is therefore of importance as differences to adult behavior are often not clarified. The aim of the present study was to investigate adolescent behavior in the multivariate concentric square field TM (MCSF) test and its relationship to other common behavioral tests as well as to a literature dataset of adult animals. Sixty adolescent male Wistar rats were tested in the MCSF and one of four reference tests; the elevated plus maze, the open field with or without start box, or the social play behavior test. Additionally, 12 animals were tested twice in the MCSF. When analyzing the first encounter with the MCSF test, a distinct grouping of the individuals into three behavioral types was observed. Approximately 20% of the animals had high levels of activity and an additional 20% had high levels of shelter seeking-behavior, these groups composed the outlying behavioral types named Explorers and Shelter seekers, respectively, which were distinct from the Main type of animals. When tested in the MCSF for a second time, the adolescent animals showed a recollection of the arena as they changed their behavior in relation to the first encounter. When comparing the MCSF performance to the reference tests, a relationship was found between the MCSF and the other behavioral test entailing forced exploration, while no relationship was found between the MCSF and social play. The adolescent behavioral profile was characterized by decreased risk assessment and a different activity profile than adults. In conclusion, the MCSF test is useful for profiling adolescent rats but the behavioral interpretation differs from that of adults due to differences in behavioral manifestation during adolescence and the presence of natural subgroups. Adolescent exploration shows a relationship across tests, but the MCSF gives more information than any of the other behavioral tests based on forced exploration. Further studies into the neurobiology behind the behavioral types and how different manipulations affect the distribution into the behavioral types are of interest.

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“…One of the most widely studied αSyn transgenic (tg) models expresses human αSyn (h-αSyn) containing the point mutation A30P, which has been found to cause PD in humans ( 11 ). The tg A30P αSyn mice present PD-like motor symptoms at around 8 months of age and there are abundant αSyn aggregates found throughout the brainstem and midbrain ( 12 – 15 ). The motor symptoms have been associated with an increase in soluble αSyn protofibrils in the spinal cord ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

In Situ Proximity Ligation Assay Reveals Co-Localization of Alpha-Synuclein and SNARE Proteins in Murine Primary Neurons

et al. 2018

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The aggregation of alpha-synuclein (αSyn) is the pathological hallmark of Parkinson’s disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of αSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between αSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human αSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human αSyn, a PLA signal indicating close proximity between αSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human αSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of αSyn and the SNARE proteins in primary neuronal cultures.

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Early fine motor impairment and behavioral dysfunction in (Thy‐1)‐h[A30P] alpha‐synuclein mice

Cited by 27 publications

References 51 publications

Targeting the N-terminus of α-synuclein Monomer Reduces Fibril-induced Aggregation in the Brain

Targeting the N-terminus of α-synuclein Monomer Reduces Fibril-induced Aggregation in the Brain

Adolescent Exploratory Strategies and Behavioral Types in the Multivariate Concentric Square FieldTM Test

In Situ Proximity Ligation Assay Reveals Co-Localization of Alpha-Synuclein and SNARE Proteins in Murine Primary Neurons

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