RESUMO
Synaptic changes are early manifestations of neuronal dysfunction in Huntington's disease (HD). However, the mechanisms by which mutant HTT protein impacts synaptogenesis and function are not well understood. Herein we explored HD pathogenesis in the BACHD mouse model by examining synaptogenesis and function in long term primary cortical cultures. At DIV14 (days in vitro), BACHD cortical neurons showed no difference from WT neurons in synaptogenesis as revealed by colocalization of a pre-synaptic (Synapsin I) and a post-synaptic (PSD95) marker. From DIV21 to DIV35, BACHD neurons showed progressively reduced colocalization of Synapsin I and PSD95 relative to WT neurons. The deficits were effectively rescued by treatment of BACHD neurons with BDNF. The recombinant apical domain of CCT1 (ApiCCT1) yielded a partial rescuing effect. BACHD neurons also showed culture age-related significant functional deficits as revealed by multielectrode arrays (MEAs). These deficits were prevented by BDNF, whereas ApiCCT1 showed a less potent effect. These findings are evidence that deficits in BACHD synapse and function can be replicated in vitro and that BDNF or a TRiC-inspired reagent can potentially be protective against these changes in BACHD neurons. Our findings support the use of cellular models to further explicate HD pathogenesis and potential treatments.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Córtex Cerebral , Modelos Animais de Doenças , Doença de Huntington , Neurônios , Sinapses , Animais , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sinapses/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Camundongos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Camundongos Transgênicos , Células Cultivadas , Sinapsinas/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Axonal degeneration is a key component of neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease, and amyotrophic lateral sclerosis. Nicotinamide, an NAD+ precursor, has long since been implicated in axonal protection and reduction of degeneration. However, studies on nicotinamide (NAm) supplementation in humans indicate that NAm has no protective effect. Sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1) regulates several cell responses to axonal damage and has been implicated in promoting neuronal degeneration. SARM1 inhibition seems to result in protection from neuronal degeneration while hydrogen peroxide has been implicated in oxidative stress and axonal degeneration. The effects of laser-induced axonal damage in wild-type and HD dorsal root ganglion cells treated with NAm, hydrogen peroxide (H2O2), and SARM1 inhibitor DSRM-3716 were investigated and the cell body width, axon width, axonal strength, and axon shrinkage post laser-induced injury were measured.
Assuntos
Doença de Huntington , Peróxido de Hidrogênio , Animais , Camundongos , Humanos , Niacinamida , Camundongos Knockout , Neurônios/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas do Domínio Armadillo/genética , Proteínas do Domínio Armadillo/metabolismoRESUMO
Climate impacts increasingly unfold in interlinked systems of people, nature, and infrastructure. The cascading consequences are revealing sometimes surprising connections across sectors and regions, and prospects for climate responses also depend on complex, difficult-to-understand interactions. In this commentary, we build on the innovations of the United States Fifth National Climate Assessment to suggest a framework for understanding and responding to complex climate challenges. This approach involves: (a) integration of disciplines and expertise to understand how intersectionality shapes complex climate impacts and the wide-ranging effects of climate responses, (b) collaborations among diverse knowledge holders to improve responses and better encompass intersectionality, and (c) sustained experimentation with and learning about governance approaches capable of handling the complexity of climate change. Together, these three pillars underscore that usability of climate-relevant knowledge requires transdisciplinary coordination of research and practice. We outline actionable steps for climate research to incorporate intersectionality, integration, and innovative governance, as is increasingly necessary for confronting climate complexity and sustaining equitable, ideally vibrant climate futures.