Neuroinflammation is one of the most important processes involved in the pathogenesis of Parkinson's disease (PD). The current concept of neuroinflammation comprises an inflammation process, which occurs in the central nervous system due to molecules released from brain-resident and/or blood-derived immune cells. Furthermore, the evidence of the contribution of systemic delivered molecules to the disease pathogenesis, such as the gut microbiota composition, has been increasing during the last years. Under physiological conditions, microglia and astrocytes support the well-being and well-function of the brain through diverse functions, including neurotrophic factor secretion in both intact and injured brain. On the other hand, genes that cause PD are expressed in astrocytes and microglia, shifting their neuroprotective role to a pathogenic one, contributing to disease onset and progression. In addition, growth factors are a subset of molecules that promote cellular survival, differentiation and maturation, which are critical signaling factors promoting the communication between cells, including neurons and blood-derived immune cells. We summarize the potential targeting of astrocytes and microglia and the systemic contribution of the gut microbiota in neuroinflammation process archived in PD.

Huntington disease (HD) is caused by an extended polyglutamine [poly(Q)] stretch in the Huntingtin (HTT) protein, and is associated with the accumulation of intracellular protein aggregates, onset of progressive chorea, psychiatric symptoms and dementia. Although the mechanism underlying the pathological effects of mutant HTT (mHTT) remains highly controversial, accumulating evidence suggest that protein-folding stress at the endoplasmic reticulum (ER) may contribute to mHTT-mediated degeneration. ER stress is alleviated by the activation of an adaptive reaction known as the unfolded protein response (UPR), whereas chronic ER stress triggers apoptosis by the same pathway. However, most of the studies linking ER stress with HD in vivo are correlative. UPR signaling is initiated by the activation of at least three distinct stress sensors located at the ER membrane known as ERN1/IRE1α, EIF2AK3/PERK and ATF6. These stress sensors control the expression of specialized transcription factors that modulate the upregulation of a variety of target genes involved in folding, protein quality control, autophagy and protein synthesis.

The biological basis of the neurodegenerative movement disorder, Parkinson’s disease (PD), is still unclear despite it being ‘discovered’ over 200 years ago in Western Medicine. Based on current PD knowledge, there are widely varying theories as to its pathobiology. The aim of this article was to explore some of these different theories by summarizing the viewpoints of laboratory and clinician scientists in the PD field, on the biological basis of the disease. To achieve this aim, we posed this question to thirteen “PD experts” from six continents (for global representation) and collated their personal opinions into this article. The views were varied, ranging from toxin exposure as a PD trigger, to LRRK2 as a potential root cause, to toxic alpha-synuclein being the most important etiological contributor. Notably, there was also growing recognition that the definition of PD as a single disease should be reconsidered, perhaps each with its own unique pathobiology and treatment regimen.

Parkinson’s disease (PD) is caused by the degeneration of dopaminergic neurons due to an accumulation of intraneuronal abnormal alpha-synuclein (α-syn) protein aggregates. It has been reported that the levels of exosomal α-syn of neuronal origin in plasma correlate significantly with motor dysfunction, highlighting the exosomes containing α-syn as a potential biomarker of PD. In addition, it has been found that the selective autophagy-lysosomal pathway (ALP) contributes to the secretion of misfolded proteins involved in neurodegenerative diseases. In this review, we describe the evidence that supports the relationship between the ALP and α-syn exosomal secretion on the PD progression and its implications in the diagnosis and progression of this pathology.

Alteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson´s and Huntington´s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.