RESUMEN
Alpha-synuclein (α-syn) aggregation and immune activation represent hallmark pathological events in Parkinson's disease (PD). The PD-associated immune response encompasses both brain and peripheral immune cells, although little is known about the immune proteins relevant for such a response. We propose that the upregulation of CD163 observed in blood monocytes and in the responsive microglia in PD patients is a protective mechanism in the disease. To investigate this, we used the PD model based on intrastriatal injections of murine α-syn pre-formed fibrils in CD163 knockout (KO) mice and wild-type littermates. CD163KO females revealed an impaired and differential early immune response to α-syn pathology as revealed by immunohistochemical and transcriptomic analysis. After 6 months, CD163KO females showed an exacerbated immune response and α-syn pathology, which ultimately led to dopaminergic neurodegeneration of greater magnitude. These findings support a sex-dimorphic neuroprotective role for CD163 during α-syn-induced neurodegeneration.
RESUMEN
Current differentiation protocols for generating mesencephalic dopaminergic (mesDA) neurons from human pluripotent stem cells result in grafts containing only a small proportion of mesDA neurons when transplanted in vivo. In this study, we develop lineage-restricted undifferentiated stem cells (LR-USCs) from pluripotent stem cells, which enhances their potential for differentiating into caudal midbrain floor plate progenitors and mesDA neurons. Using a ventral midbrain protocol, 69% of LR-USCs become bona fide caudal midbrain floor plate progenitors, compared to only 25% of human embryonic stem cells (hESCs). Importantly, LR-USCs generate significantly more mesDA neurons under midbrain and hindbrain conditions in vitro and in vivo. We demonstrate that midbrain-patterned LR-USC progenitors transplanted into 6-hydroxydopamine-lesioned rats restore function in a clinically relevant non-pharmacological behavioral test, whereas midbrain-patterned hESC-derived progenitors do not. This strategy demonstrates how lineage restriction can prevent the development of undesirable lineages and enhance the conditions necessary for mesDA neuron generation.
Asunto(s)
Neuronas Dopaminérgicas , Células Madre Pluripotentes , Humanos , Ratas , Animales , Neuronas Dopaminérgicas/metabolismo , Factores de Transcripción/metabolismo , Diferenciación Celular/fisiología , Mesencéfalo , Células Madre Pluripotentes/metabolismoRESUMEN
Multiple lines of clinical and pre-clinical research support a pathogenic role for neuroinflammation and peripheral immune system dysfunction in Parkinson's disease. In this paper, we have reviewed and summarised the published literature reporting evidence of neuroinflammation and peripheral immune changes in cohorts of patients with isolated REM sleep behaviour disorder and non-manifesting carriers of GBA or LRRK2 gene mutations, who have increased risk for Parkinsonism and synucleinopathies, and could be in the prodromal stage of these conditions. Taken together, the findings of these studies suggest that the early stages of pathology in Parkinsonism involve activation of both the central and peripheral immune systems with significant crosstalk. We consider these findings with respect to those found in patients with clinical Parkinson's disease and discuss their possible pathological roles. Moreover, those factors possibly associated with the immune response, such as the immunomodulatory role of the affected neurotransmitters and the changes in the gut-brain axis, are also considered.
