Chronic corticosterone aggravates behavioral and neuronal symptomatology in a mouse model of alpha-synuclein pathology

Burtscher, Johannes; Copin, Jean‐Christophe; Rodrigues, João; Kumar, Senthil T.; Chiki, Anass; Suduiraut, Isabelle Guillot de; Sandi, Carmen; Lashuel, Hilal A.

doi:10.1016/j.neurobiolaging.2019.08.007

Cited by 34 publications

(38 citation statements)

References 85 publications

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“…1C). We observed similar pathology patterns in PFF-groups, irrespective of corticosterone treatment as reported previously (Burtscher et al, 2019).…”

Section: Resultssupporting

confidence: 91%

“…Following up on our findings that α-synuclein pathology in mouse amygdala did not cause strong behavioral deficits (Burtscher et al, 2019), we interrogated here, whether α-synuclein pathology, as defined above, was sufficient to cause mitochondrial dysfunction in the amygdala or at the site of injection (striatum). In the applied model, histological staining of pS129 α-synuclein suggests pathology to peak between 1-3 months in the amygdala and decrease thereafter.…”

Section: Discussionmentioning

confidence: 99%

“…α-synuclein fibrils were prepared and characterized as described previously (Burtscher et al, 2019; Kumar et al, 2020). Brieflly, a 325 μM solution of pure mouse α-synuclein recombinant protein (in PBS, pH7.2) was centrifuged in filter tubes of 0.2 μM (5 min, 5000 rpm).…”

Section: Methodsmentioning

confidence: 99%

“…α-synuclein pathology seeding in rodents by inoculation of the striatum (Luk et al, 2012) or the olfactory bulb (Rey et al, 2016) with PFFs results in strong α-synuclein pathology in the amygdala (Burtscher et al, 2019), reminiscent of human synucleinopathy (Nelson et al, 2018; Sorrentino et al, 2019). Recently, we reported subtle behavioral effects related to this pronounced α-synuclein pathology in the mouse amygdala (Burtscher et al, 2019), with little influence of additional exogenous corticosterone induced amygdala-related mood deficits, modelling prodromal mood symptoms in PD. Metabolic alterations in the amygdala have been reported upon chronic glucocorticoid administration (Thobois et al, 2017), thus we hypothesized that mitochondrial dysfunction might precede behavioral deficits.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we assessed, whether α-synuclein pathology at early time points (5-6 weeks) after seeding in the amygdala would suffice to induce mitochondrial dysfunction and whether additional chronic corticosterone would further exacerbate mitochondrial dysfunction. We chose this time point because this is when we see maximum α-synuclein pathology (pS129 immunoreactivity) in the amygdala (Burtscher et al, 2019). Originally, continuously increasing α-synuclein pathology in the amygdala has been assumed after injection in the striatum (Luk et al, 2012) or olfactory bulb (Rey et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

Burtscher

Copin

Sandi³

et al. 2020

Preprint

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Increasing evidence suggests that crosstalk between α-synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinson’s disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinson’s disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology.Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala.We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinson’s disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as α-synuclein pathology in male mice.Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions.Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model.Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinson’s disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of α-synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.

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“…1C). We observed similar pathology patterns in PFF-groups, irrespective of corticosterone treatment as reported previously (Burtscher et al, 2019).…”

Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

Burtscher

Copin

Sandi³

et al. 2020

Preprint

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Targeting Lewy body dementia with neflamapimod‐rasagiline hybrids

Albertini,

Petralla,

Massenzio

et al. 2024

Archiv der Pharmazie

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Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain‐penetrant selective inhibitor of the alpha isoform of the mitogen‐activated serine/threonine protein kinase (MAPK) p38α, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of 1 and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6‐dichlorophenyl ring of 1, generating neflamapimod‐propargylamine hybrids 3 and 4. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The N‐methyl‐N‐propargyl derivative 4 showed a nanomolar p38α‐MAPK inhibitory activity (IC50 = 98.7 nM), which is only 2.6‐fold lower compared to that of the parent compound 1, while displaying no hepato‐ and neurotoxicity up to 25 μM concentration. It also retained a similar immunomodulatory profile against the N9 microglial cell line. Gratifyingly, at 5 μM concentration, 4 demonstrated a neuroprotective effect against dexamethasone‐induced reactive oxygen species production in neuronal cells that was higher than that of 1.

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Stress and Mindfulness in Parkinson's Disease: Clinical Effects and Potential Underlying Mechanisms

Heide

Meinders²,

Speckens

et al. 2020

Movement Disorders

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Patients with Parkinson's disease (PD) are very vulnerable to the negative effects of psychological distress: neuropsychiatric symptoms, such as anxiety and depression, are highly prevalent in PD; motor symptoms (such as tremor) typically worsen in stressful situations; and dopaminergic medication is less effective. Furthermore, animal studies of PD suggest that chronic stress may accelerate disease progression. Adequate self‐management strategies are therefore essential to reduce the detrimental effects of chronic stress on PD. Mindfulness‐based interventions encourage individuals to independently self‐manage and adapt to the challenges created by their condition. In PD, emerging clinical evidence suggests that mindfulness‐based interventions may reduce psychological distress and improve clinical symptoms, but insight into the underlying mechanisms is lacking. In this viewpoint, we provide a systematic overview of existing mindfulness trials in PD. Furthermore, we discuss the cerebral mechanisms involved in acute and chronic stress, and the impact of mindfulness‐based interventions on these networks. In addition, we delineate a hypothetical mechanistic framework of how chronic stress may increase the susceptibility for neuropsychiatric symptoms in PD and may potentially even influence disease progression. We end with offering recommendations for future research. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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Chronic corticosterone aggravates behavioral and neuronal symptomatology in a mouse model of alpha-synuclein pathology

Cited by 34 publications

References 85 publications

Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

Targeting Lewy body dementia with neflamapimod‐rasagiline hybrids

Stress and Mindfulness in Parkinson's Disease: Clinical Effects and Potential Underlying Mechanisms

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