Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells.

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.

The systemic immune response in Parkinson's disease: focus on the peripheral immune component.

During Parkinson's disease (PD), both the central nervous system (CNS) and peripheral nervous system (PNS) are affected. In parallel, innate immune cells respond early to neuronal changes and alpha-synuclein (α-syn) pathology. Moreover, some of the affected neuronal groups innervate organs with a relevant role in immunity. Consequently, not only microglia, but also peripheral immune cells are altered, resulting in a systemic immune response. Innate and adaptive immune cells may participate in the neurodegenerative process by acting peripherally, infiltrating the brain, or releasing mediators that can protect or harm neurons. However, the sequence of the changes and the significance of each immune compartment in the disease remain to be clarified. In this review, we describe current understanding of the peripheral immune response in PD and discuss the road ahead.

Neuroinflammation and Immune Changes in Prodromal Parkinson's Disease and Other Synucleinopathies.

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.