RESUMO
Heterozygous point mutations of α-synuclein (α-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) α-syn and its role in the exacerbated pathology of α-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant α-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different α-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryo-electron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT α-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT α-syn in such a way that the mutant pathology would be amplified in fPD.
Assuntos
Amiloide/genética , Mutação de Sentido Incorreto , Doenças do Sistema Nervoso/genética , Doença de Parkinson/genética , Agregação Patológica de Proteínas/genética , alfa-Sinucleína/genética , Amiloide/metabolismo , Amiloide/ultraestrutura , Animais , Microscopia Crioeletrônica , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Força Atômica , Microscopia Confocal , Atividade Motora/genética , Atividade Motora/fisiologia , Doenças do Sistema Nervoso/metabolismo , Doença de Parkinson/metabolismo , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/química , alfa-Sinucleína/metabolismoRESUMO
The arousal state of the brain covaries with the motor state of the animal. How these state changes are coordinated remains unclear. We discovered that sleep-wake brain states and motor behaviors are coregulated by shared neurons in the substantia nigra pars reticulata (SNr). Analysis of mouse home-cage behavior identified four states with different levels of brain arousal and motor activity: locomotion, nonlocomotor movement, quiet wakefulness, and sleep; transitions occurred not randomly but primarily between neighboring states. The glutamic acid decarboxylase 2 but not the parvalbumin subset of SNr γ-aminobutyric acid (GABA)-releasing (GABAergic) neurons was preferentially active in states of low motor activity and arousal. Their activation or inactivation biased the direction of natural behavioral transitions and promoted or suppressed sleep, respectively. These GABAergic neurons integrate wide-ranging inputs and innervate multiple arousal-promoting and motor-control circuits through extensive collateral projections.
