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Neurodegenerative disorders such as Parkinson’s (PD) and Huntington’s disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.

Huntington’s disease (HD) is an inherited neurodegenerative disorder in which the striatum is the most affected brain region. Although a chronic inflammatory microglial reaction that amplifies disease progression has been described in HD patients, some murine models develop symptoms without inflammatory microglial activation. Thus, dysfunction of non-inflammatory microglial activity could also contribute to the early HD pathological process. Here, we show the involvement of microglia and particularly fractalkine signaling in the striatal synaptic dysfunction of R6/1 mice. We found reduced fractalkine gene expression and protein concentration in R6/1 striata from 8 to 20 weeks of age. Consistently, we also observed a down-regulation of fractalkine levels in the putamen of HD patients and in HD patient hiPSC-derived neurons. Automated cell morphology analysis showed a non-inflammatory ramified microglia in the striatum of R6/1 mice. However, we found increased PSD-95-positive puncta inside microglia, indicative of synaptic pruning, before HD motor symptoms start to manifest. Indeed, microglia appeared to be essential for striatal synaptic function, as the inhibition of microglial activity with minocycline impaired the induction of corticostriatal long-term depression (LTD) in wild-type mice. Notably, fractalkine administration restored impaired corticostriatal LTD in R6/1 mice. Our results unveil a role for fractalkine-dependent neuron-microglia interactions in the early striatal synaptic dysfunction characteristic of HD.

The role of the WDFY1 protein has been studied as a TLR3/4 scaffold/recruiting protein in the immune system and in different oncogenic conditions. However, its function in brain remains poorly understood. We have found that in mice devoid of Helios (He–/– mice), a transcription factor specifically expressed during the development of the immune cells and the central nervous system, there is a permanent and sustained increase of Wdfy1 gene expression in the striatum and hippocampus. Interestingly, we observed that WDFY1 protein levels were also increased in the hippocampus and dorsolateral prefrontal cortex of schizophrenic patients, but not in the hippocampus of Alzheimer’s disease patients with an associated psychotic disorder. Accordingly, young He–/– mice displayed several schizophrenic-like behaviors related to dysfunctions in the striatum and hippocampus. These changes were associated with an increase in spine density in medium spiny neurons (MSNs) and with a decrease in the number and size of PSD-95-positive clusters in the stratum radiatum of the CA1. Moreover, these alterations in structural synaptic plasticity were associated with a strong reduction of neuronal NF-κB in the pyramidal layer of the CA1 in He–/– mice. Altogether, our data indicate that alterations involving the molecular axis Helios-WDFY1 in neurons during the development of core brain regions could be relevant for the pathophysiology of neuropsychiatric disorders such as schizophrenia.