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1.
Neuron ; 103(4): 627-641.e7, 2019 08 21.
Article in English | MEDLINE | ID: mdl-31255487

ABSTRACT

Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).


Subject(s)
Axonal Transport , Parkinsonian Disorders/etiology , Protein Aggregates , Vagus Nerve/metabolism , alpha-Synuclein/pharmacokinetics , Animals , Brain Chemistry , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Duodenum/innervation , Duodenum/metabolism , Humans , Injections, Intramuscular , Lewy Bodies/metabolism , Maze Learning , Memory Disorders/etiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Neurological , Muscle, Smooth/innervation , Muscle, Smooth/metabolism , Nesting Behavior/physiology , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/prevention & control , Parkinsonian Disorders/psychology , Phosphorylation , Protein Processing, Post-Translational , Pylorus/innervation , Pylorus/metabolism , Rotarod Performance Test , Vagotomy , alpha-Synuclein/administration & dosage , alpha-Synuclein/deficiency , alpha-Synuclein/toxicity
2.
Hum Mol Genet ; 27(13): 2344-2356, 2018 07 01.
Article in English | MEDLINE | ID: mdl-29897434

ABSTRACT

Accumulating evidence suggests that the non-receptor tyrosine kinase c-Abl plays an important role in the progression of Parkinson's disease (PD) and c-Abl inhibition could be neuroprotective in PD and related α-synucleinopathies. Nilotinib, a c-Abl inhibitor, has shown improved motor and cognitive symptoms in PD patients. However, issues concerning blood-brain barrier (BBB) penetration, lack of selectivity and safety still remain. Radotinib HCl is a selective Bcr-Abl kinase inhibitor that not only effectively access the brain, but also exhibits greater pharmacokinetic properties and safety profiles compared to Nilotinib and other c-Abl inhibitors. Here, we show the neuroprotective efficacy of Radotinib HCl, a brain penetrant c-Abl inhibitor, in a pre-clinical model of PD. Importantly, in vitro studies demonstrate that the treatment of Radotinib HCl protects the α-synuclein preformed fibrils (PFF)-induced neuronal toxicity, reduces the α-synuclein PFF-induced Lewy bodies (LB)/Lewy neurites (LN)-like pathology and inhibits the α-synuclein PFF-induced c-Abl activation in primary cortical neurons. Furthermore, administration of Radotinib HCl inhibits c-Abl activation and prevents dopaminergic neuron loss, neuroinflammation and behavioral deficits following α-synuclein PFF-induced toxicity in vivo. Taken together, our findings indicate that Radotinib HCl has beneficial neuroprotective effects in PD and provides an evidence that selective and brain permeable c-Abl inhibitors can be potential therapeutic agents for the treatment of PD and related α-synucleinopathies.


Subject(s)
Brain/drug effects , Nerve Degeneration/drug therapy , Parkinson Disease/drug therapy , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , alpha-Synuclein/genetics , Animals , Blood-Brain Barrier , Brain/metabolism , Disease Models, Animal , Dopamine/metabolism , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Humans , Lewy Bodies/drug effects , Mice , Nerve Degeneration/genetics , Neuroprotective Agents/administration & dosage , Parkinson Disease/genetics , Parkinson Disease/pathology , Proto-Oncogene Proteins c-abl/genetics , Pyrimidines/administration & dosage , Sesquiterpenes/administration & dosage
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