Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei

Vasileios Theologidis; Sara A Ferreira; Nanna M Jensen; Diana Gomes Moreira; Ole A Ahlgreen; Mads W Hansen; Emilie D Rosenberg; Mette Richner; Islam Faress; Hjalte Gram; Poul Henning Jensen; Per Borghammer; Jens R Nyengaard; Marina Romero-Ramos; Christian B Vægter; Wilma D J van de Berg; Nathalie Van Den Berge; Asad Jan

doi:10.1186/s40478-025-01948-7

Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei

Vasileios Theologidis, Sara A Ferreira, Nanna M Jensen, Diana Gomes Moreira, Ole A Ahlgreen, Mads W Hansen, Emilie D Rosenberg, Mette Richner, Islam Faress, Hjalte Gram, Poul Henning Jensen, Per Borghammer, Jens R Nyengaard, Marina Romero-Ramos, Christian B Vægter, Wilma D J van de Berg, Nathalie Van Den Berge, Asad Jan

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

α-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in the brainstem, including the gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during the prodromal phase of Parkinson disease (PD). Accordingly, there is a burgeoning interest in animal model development for understanding the pathological significance of extra-nigral synucleinopathy, in relation to motor and/or non-motor symptomatology in PD. Here, we report an experimental paradigm for the induction of aSyn aggregation in brainstem, with stereotaxic delivery of pre-formed fibrillar (PFF) aSyn in the pontine GRN of transgenic mice expressing the mutant human Ala53Thr aSyn (M83 line). Our data show that PFF aSyn-induced aggregate pathology in GRN and distinct nuclei of subcortical motor system leads to progressive decline in home cage activity, which was accompanied by postural instability and impaired motor coordination. The progressive accumulation of aSyn pathology in brainstem and motor neurons in lumbar spinal cord heralded the onset of a moribund stage, which culminated in impaired survival. Collectively, our observations suggest an experimental framework for studying the pathological significance of aSyn aggregation in GRN in relation to features of movement disability in PD. With further refinements, we anticipate that this model holds promise as a test-bed for translational research in PD and related disorders.

Originalsprog	Engelsk
Artikelnummer	32
Tidsskrift	Acta Neuropathologica Communications
Vol/bind	13
Nummer	1
Sider (fra-til)	32
Antal sider	1
ISSN	2051-5960
DOI	https://doi.org/10.1186/s40478-025-01948-7
Status	Udgivet - 17 feb. 2025

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10.1186/s40478-025-01948-7

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Theologidis, V., Ferreira, S. A., Jensen, N. M., Gomes Moreira, D., Ahlgreen, O. A., Hansen, M. W., Rosenberg, E. D., Richner, M., Faress, I., Gram, H., Jensen, P. H., Borghammer, P., Nyengaard, J. R., Romero-Ramos, M., Vægter, C. B., van de Berg, W. D. J., Van Den Berge, N., & Jan, A. (2025). Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei. Acta Neuropathologica Communications, 13(1), 32. Artikel 32. https://doi.org/10.1186/s40478-025-01948-7

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title = "Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei",

abstract = "α-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in the brainstem, including the gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during the prodromal phase of Parkinson disease (PD). Accordingly, there is a burgeoning interest in animal model development for understanding the pathological significance of extra-nigral synucleinopathy, in relation to motor and/or non-motor symptomatology in PD. Here, we report an experimental paradigm for the induction of aSyn aggregation in brainstem, with stereotaxic delivery of pre-formed fibrillar (PFF) aSyn in the pontine GRN of transgenic mice expressing the mutant human Ala53Thr aSyn (M83 line). Our data show that PFF aSyn-induced aggregate pathology in GRN and distinct nuclei of subcortical motor system leads to progressive decline in home cage activity, which was accompanied by postural instability and impaired motor coordination. The progressive accumulation of aSyn pathology in brainstem and motor neurons in lumbar spinal cord heralded the onset of a moribund stage, which culminated in impaired survival. Collectively, our observations suggest an experimental framework for studying the pathological significance of aSyn aggregation in GRN in relation to features of movement disability in PD. With further refinements, we anticipate that this model holds promise as a test-bed for translational research in PD and related disorders.",

keywords = "Animals, Brain Stem/metabolism, Disease Models, Animal, Humans, Hypokinesia/pathology, Male, Mice, Mice, Transgenic, Postural Balance/physiology, Prodromal Symptoms, Protein Aggregation, Pathological/metabolism, Synucleinopathies/pathology, alpha-Synuclein/metabolism, Parkinson disease, Gigantocellular nucleus, Lewy pathology, Αlpha-synuclein",

author = "Vasileios Theologidis and Ferreira, {Sara A} and Jensen, {Nanna M} and {Gomes Moreira}, Diana and Ahlgreen, {Ole A} and Hansen, {Mads W} and Rosenberg, {Emilie D} and Mette Richner and Islam Faress and Hjalte Gram and Jensen, {Poul Henning} and Per Borghammer and Nyengaard, {Jens R} and Marina Romero-Ramos and V{\ae}gter, {Christian B} and {van de Berg}, {Wilma D J} and {Van Den Berge}, Nathalie and Asad Jan",

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day = "17",

doi = "10.1186/s40478-025-01948-7",

language = "English",

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pages = "32",

journal = "Acta Neuropathologica Communications",

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Theologidis, V , Ferreira, SA , Jensen, NM, Gomes Moreira, D, Ahlgreen, OA , Hansen, MW , Rosenberg, ED , Richner, M , Faress, I , Gram, H , Jensen, PH , Borghammer, P , Nyengaard, JR , Romero-Ramos, M , Vægter, CB, van de Berg, WDJ, Van Den Berge, N & Jan, A 2025, 'Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei', Acta Neuropathologica Communications, bind 13, nr. 1, 32, s. 32. https://doi.org/10.1186/s40478-025-01948-7

Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei. / Theologidis, Vasileios ; Ferreira, Sara A ; Jensen, Nanna M et al.
I: Acta Neuropathologica Communications, Bind 13, Nr. 1, 32, 17.02.2025, s. 32.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei

AU - Theologidis, Vasileios

AU - Ferreira, Sara A

AU - Jensen, Nanna M

AU - Gomes Moreira, Diana

AU - Ahlgreen, Ole A

AU - Hansen, Mads W

AU - Rosenberg, Emilie D

AU - Richner, Mette

AU - Faress, Islam

AU - Gram, Hjalte

AU - Jensen, Poul Henning

AU - Borghammer, Per

AU - Nyengaard, Jens R

AU - Romero-Ramos, Marina

AU - Vægter, Christian B

AU - van de Berg, Wilma D J

AU - Van Den Berge, Nathalie

AU - Jan, Asad

PY - 2025/2/17

Y1 - 2025/2/17

N2 - α-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in the brainstem, including the gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during the prodromal phase of Parkinson disease (PD). Accordingly, there is a burgeoning interest in animal model development for understanding the pathological significance of extra-nigral synucleinopathy, in relation to motor and/or non-motor symptomatology in PD. Here, we report an experimental paradigm for the induction of aSyn aggregation in brainstem, with stereotaxic delivery of pre-formed fibrillar (PFF) aSyn in the pontine GRN of transgenic mice expressing the mutant human Ala53Thr aSyn (M83 line). Our data show that PFF aSyn-induced aggregate pathology in GRN and distinct nuclei of subcortical motor system leads to progressive decline in home cage activity, which was accompanied by postural instability and impaired motor coordination. The progressive accumulation of aSyn pathology in brainstem and motor neurons in lumbar spinal cord heralded the onset of a moribund stage, which culminated in impaired survival. Collectively, our observations suggest an experimental framework for studying the pathological significance of aSyn aggregation in GRN in relation to features of movement disability in PD. With further refinements, we anticipate that this model holds promise as a test-bed for translational research in PD and related disorders.

AB - α-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in the brainstem, including the gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during the prodromal phase of Parkinson disease (PD). Accordingly, there is a burgeoning interest in animal model development for understanding the pathological significance of extra-nigral synucleinopathy, in relation to motor and/or non-motor symptomatology in PD. Here, we report an experimental paradigm for the induction of aSyn aggregation in brainstem, with stereotaxic delivery of pre-formed fibrillar (PFF) aSyn in the pontine GRN of transgenic mice expressing the mutant human Ala53Thr aSyn (M83 line). Our data show that PFF aSyn-induced aggregate pathology in GRN and distinct nuclei of subcortical motor system leads to progressive decline in home cage activity, which was accompanied by postural instability and impaired motor coordination. The progressive accumulation of aSyn pathology in brainstem and motor neurons in lumbar spinal cord heralded the onset of a moribund stage, which culminated in impaired survival. Collectively, our observations suggest an experimental framework for studying the pathological significance of aSyn aggregation in GRN in relation to features of movement disability in PD. With further refinements, we anticipate that this model holds promise as a test-bed for translational research in PD and related disorders.

KW - Animals

KW - Brain Stem/metabolism

KW - Disease Models, Animal

KW - Humans

KW - Hypokinesia/pathology

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Postural Balance/physiology

KW - Prodromal Symptoms

KW - Protein Aggregation, Pathological/metabolism

KW - Synucleinopathies/pathology

KW - alpha-Synuclein/metabolism

KW - Parkinson disease

KW - Gigantocellular nucleus

KW - Lewy pathology

KW - Αlpha-synuclein

UR - http://www.scopus.com/inward/record.url?scp=85218959105&partnerID=8YFLogxK

U2 - 10.1186/s40478-025-01948-7

DO - 10.1186/s40478-025-01948-7

M3 - Journal article

C2 - 39962601

SN - 2051-5960

VL - 13

SP - 32

JO - Acta Neuropathologica Communications

JF - Acta Neuropathologica Communications

IS - 1

M1 - 32

ER -

Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei

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