Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein

Dilshan S. Harischandra, Dharmin Rokad, Matthew L. Neal, Shivani Ghaisas, Sireesha Manne, Souvarish Sarkar, Nikhil Panicker, Gary Zenitsky, Huajun Jin, Mechelle Lewis, Xuemei Huang, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy

Research output: Contribution to journalArticle

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Abstract

The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn 2+ ) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson's disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn 2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn 2+ -elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn 2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn 2+ exposure. Welders exposed to Mn 2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn 2+ -treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn 2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.

Original languageEnglish (US)
Article numbereaau4543
JournalScience signaling
Volume12
Issue number572
DOIs
StatePublished - Jan 1 2019

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Synucleins
Prions
Manganese
Agglomeration
Exosomes
Caveolae
Parkinsonian Disorders
Pathology
Endocytosis
Mountings
Cell culture
Neurodegenerative Diseases

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Harischandra, D. S., Rokad, D., Neal, M. L., Ghaisas, S., Manne, S., Sarkar, S., ... Kanthasamy, A. G. (2019). Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein. Science signaling, 12(572), [eaau4543]. https://doi.org/10.1126/scisignal.aau4543
Harischandra, Dilshan S. ; Rokad, Dharmin ; Neal, Matthew L. ; Ghaisas, Shivani ; Manne, Sireesha ; Sarkar, Souvarish ; Panicker, Nikhil ; Zenitsky, Gary ; Jin, Huajun ; Lewis, Mechelle ; Huang, Xuemei ; Anantharam, Vellareddy ; Kanthasamy, Arthi ; Kanthasamy, Anumantha G. / Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein. In: Science signaling. 2019 ; Vol. 12, No. 572.
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abstract = "The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn 2+ ) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson's disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn 2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn 2+ -elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn 2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn 2+ exposure. Welders exposed to Mn 2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn 2+ -treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn 2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.",
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Harischandra, DS, Rokad, D, Neal, ML, Ghaisas, S, Manne, S, Sarkar, S, Panicker, N, Zenitsky, G, Jin, H, Lewis, M, Huang, X, Anantharam, V, Kanthasamy, A & Kanthasamy, AG 2019, 'Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein', Science signaling, vol. 12, no. 572, eaau4543. https://doi.org/10.1126/scisignal.aau4543

Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein. / Harischandra, Dilshan S.; Rokad, Dharmin; Neal, Matthew L.; Ghaisas, Shivani; Manne, Sireesha; Sarkar, Souvarish; Panicker, Nikhil; Zenitsky, Gary; Jin, Huajun; Lewis, Mechelle; Huang, Xuemei; Anantharam, Vellareddy; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

In: Science signaling, Vol. 12, No. 572, eaau4543, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein

AU - Harischandra, Dilshan S.

AU - Rokad, Dharmin

AU - Neal, Matthew L.

AU - Ghaisas, Shivani

AU - Manne, Sireesha

AU - Sarkar, Souvarish

AU - Panicker, Nikhil

AU - Zenitsky, Gary

AU - Jin, Huajun

AU - Lewis, Mechelle

AU - Huang, Xuemei

AU - Anantharam, Vellareddy

AU - Kanthasamy, Arthi

AU - Kanthasamy, Anumantha G.

PY - 2019/1/1

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N2 - The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn 2+ ) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson's disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn 2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn 2+ -elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn 2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn 2+ exposure. Welders exposed to Mn 2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn 2+ -treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn 2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.

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