Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit.
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Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit. / Gonzalez-Reyes, Luis E; Verbitsky, Miguel; Blesa, Javier; Jackson-Lewis, Vernice; Paredes, Daniel; Tillack, Karsten; Phani, Sudarshan; Kramer, Edgar; Przedborski, Serge; Kottmann, Andreas H.
in: NEURON, Jahrgang 75, Nr. 2, 2, 2012, S. 306-319.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit.
AU - Gonzalez-Reyes, Luis E
AU - Verbitsky, Miguel
AU - Blesa, Javier
AU - Jackson-Lewis, Vernice
AU - Paredes, Daniel
AU - Tillack, Karsten
AU - Phani, Sudarshan
AU - Kramer, Edgar
AU - Przedborski, Serge
AU - Kottmann, Andreas H
PY - 2012
Y1 - 2012
N2 - Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non cell-autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson's disease. Variable Shh signaling results in graded inhibition of muscarinic autoreceptor- and glial cell line-derived neurotrophic factor (GDNF)-expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson's disease.
AB - Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non cell-autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson's disease. Variable Shh signaling results in graded inhibition of muscarinic autoreceptor- and glial cell line-derived neurotrophic factor (GDNF)-expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson's disease.
KW - Animals
KW - Mice
KW - Motor Activity/physiology
KW - Signal Transduction/physiology
KW - Hedgehog Proteins/genetics/metabolism
KW - Cholinergic Neurons/metabolism/pathology
KW - Corpus Striatum/metabolism/pathology
KW - Dopaminergic Neurons/metabolism/pathology
KW - GABAergic Neurons/metabolism/pathology
KW - Gait/physiology
KW - Glial Cell Line-Derived Neurotrophic Factor/metabolism
KW - Homeostasis/physiology
KW - Nerve Degeneration/genetics/metabolism/pathology
KW - Neural Pathways/metabolism/pathology
KW - Parkinson Disease/genetics/metabolism/pathology
KW - Substantia Nigra/metabolism/pathology
KW - Animals
KW - Mice
KW - Motor Activity/physiology
KW - Signal Transduction/physiology
KW - Hedgehog Proteins/genetics/metabolism
KW - Cholinergic Neurons/metabolism/pathology
KW - Corpus Striatum/metabolism/pathology
KW - Dopaminergic Neurons/metabolism/pathology
KW - GABAergic Neurons/metabolism/pathology
KW - Gait/physiology
KW - Glial Cell Line-Derived Neurotrophic Factor/metabolism
KW - Homeostasis/physiology
KW - Nerve Degeneration/genetics/metabolism/pathology
KW - Neural Pathways/metabolism/pathology
KW - Parkinson Disease/genetics/metabolism/pathology
KW - Substantia Nigra/metabolism/pathology
M3 - SCORING: Journal article
VL - 75
SP - 306
EP - 319
JO - NEURON
JF - NEURON
SN - 0896-6273
IS - 2
M1 - 2
ER -
