RESUMO
Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.
Assuntos
Modelos Animais de Doenças , Proteínas de Homeodomínio/genética , Doença de Parkinson/genética , Locos de Características Quantitativas/genética , Animais , Neurônios Dopaminérgicos/metabolismo , Feminino , Predisposição Genética para Doença/genética , Heterozigoto , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças Neurodegenerativas/genética , Neuropatologia , Substância Negra/metabolismo , Substância Negra/patologiaRESUMO
Recent research suggests that in Parkinson's disease the long, thin and unmyelinated axons of dopaminergic neurons degenerate early in the disease process. We organized a workshop entitled 'Axonal Pathology in Parkinson's disease', on March 23rd, 2016, in Cleveland, Ohio with the goals of summarizing the state-of-the-art and defining key gaps in knowledge. A group of eight research leaders discussed new developments in clinical pathology, functional imaging, animal models, and mechanisms of degeneration including neuroinflammation, autophagy and axonal transport deficits. While the workshop focused on PD, comparisons were made to other neurological conditions where axonal degeneration is well recognized.
Assuntos
Axônios/patologia , Congressos como Assunto , Neurônios Dopaminérgicos/patologia , Doença de Parkinson/patologia , Animais , HumanosRESUMO
We demonstrate that grafted human fetal mesencephalic neurons can survive and extend axons for 22 years in the brain of a patient with Parkinson's disease (PD). In this patient, the overall survival and fiber outgrowth of the grafts were, however, relatively poor, which is consistent with the lack of significant clinical graft-induced benefit. We have compared the morphology of neurons in the 22-year old grafts with those in two younger grafts (16- and 12-year old), which were sequentially implanted in another PD patient. In the case with the 22-year-old transplant, a high proportion (up to 38%) of the grafted dopaminergic (pigment-granule containing) neurons do not express tyrosine hydroxylase and dopamine transporter and their perikarya appear atrophic. The proportion of pigmented neurons not expressing these markers is lower in the 12-16 year old grafts. Furthermore, in the 22-year-old graft, 49% of the pigmented neurons display α-synuclein immunoreactivity in the cell body and 1.2% of them contain Lewy bodies. In conclusion, our results show that grafted dopaminergic neurons can survive for more than two decades. However, over time an increasing proportion of grafted neurons exhibit signs of degeneration.
