Cold Spring Harbor perspectives in medicine最新文献

Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut-brain axis for the development of biomarkers and disease-modifying treatments.

Tumor cells divide rapidly and dramatically alter their metabolism to meet biosynthetic and bioenergetic needs. Through studying the aberrant metabolism of cancer cells, other contexts in which metabolism drives cell state transitions become apparent. In this work, we will discuss how principles established by the field of cancer metabolism have led to discoveries in the contexts of physiology and tissue injury, mammalian embryonic development, and virus infection. We present specific examples of findings from each of these fields that have been shaped by the study of cancer metabolism. We also discuss the next important scientific questions facing these subject areas collectively. Altogether, these examples demonstrate that the study of "cancer metabolism" is indeed the study of cell metabolism in the context of a tumor, and undoubtedly discoveries from each of the fields discussed here will continue to build on each other in the future.

Rhabdomyosarcoma (RMS) is a pediatric embryonal solid tumor and the most common pediatric soft tissue sarcoma. The histology and transcriptome of RMS resemble skeletal muscle progenitor cells that have failed to terminally differentiate. Thus, RMS is typically thought to arise from corrupted skeletal muscle progenitor cells during development. However, RMS can occur in body regions devoid of skeletal muscle, suggesting the potential for nonmyogenic cells of origin. Here, we discuss the interplay between RMS driver mutations and cell(s) of origin with an emphasis on driving location specificity. Additionally, we discuss the mechanisms governing RMS transformation events and tumor heterogeneity through the lens of transcriptional networks and epigenetic control. Finally, we reimagine Waddington's developmental landscape to include a plane of transformation connecting distinct lineage landscapes to more accurately reflect the phenomena observed in pediatric cancers.

Epigenetic therapies are emerging for pediatric cancers. Due to the relatively low mutational burden in pediatric tumors, epigenetic dysregulation and differentiation blockade is a hallmark of oncogenesis in some childhood cancers. By targeting epigenetic regulators that maintain tumor cells in a primitive developmental state, epigenetic therapies may induce differentiation. The most well-studied and clinically advanced epigenetic-targeted therapies include azacitidine and decitabine, which inhibit DNA methylation through competitive inhibition of the enzymatic activity of the DNA methyltransferase family enzymes. These DNA hypomethylating agents are Food and Drug Administration (FDA) approved for hematologic malignancies. The discovery that DNA hypermethylation occurs in patients with isocitrate dehydrogenase (IDH) mutations has led to the development and FDA approval of IDH inhibitors for hematologic and solid tumors. Epigenetic dysregulation in pediatric tumors is also driven by changes in the "histone code" that either promote oncogene expression or repress tumor suppressors. Cancers whose chromatin landscape is characterized by such aberrant histone posttranslational modifications may be amenable to targeted therapies that inhibit the chromatin-modifying enzymes that read, write, and erase these histone modifications. Small molecules that inhibit the enzymatic activity of histone deacetylases, acetyltransferases, and methyltransferases have been approved for the treatment of some adult cancers, and these agents are currently under investigation in various pediatric tumors. Chromatin regulatory complexes can be hijacked by oncogenic fusion proteins that are produced by chromosomal translocations, which are common drivers in pediatric cancer. Small molecules that disrupt oncogenic fusion protein activity and their associated chromatin complexes have demonstrated remarkable promise, and this approach has become the standard treatment for a subset of leukemias driven by the PML-RARA oncogenic fusion protein. A deeper understanding of the mechanisms that drive epigenetic dysregulation in pediatric cancer may hold the key to future success in this field, as the landscape of druggable epigenetic targets is also expanding.

Autophagy is a vital cellular process responsible for the degradation of proteins, organelles, and other cellular components within lysosomes. In neurons, basal autophagy is indispensable for maintaining cellular homeostasis and protein quality control. Accordingly, lysosomal dysfunction has been proposed to be associated with neurodegeneration, and with Parkinson's disease (PD) in particular. Aging, dopamine metabolism, and PD-linked genetic mutations are thought to impair the autophagic-lysosomal pathway, disrupt cellular proteostasis, and contribute to PD pathogenesis. These alterations represent an opportunity to identify potential new therapeutic targets and disease biomarkers, thus laying the groundwork for the development of novel disease-modifying strategies for PD that are aimed at restoring cellular proteostasis and quality control systems.

Research in the last few decades has brought us closer to an understanding of the brain circuit abnormalities that underlie parkinsonian motor signs. This article summarizes the current knowledge in this rapidly emerging field. Traditional observations of activity changes of basal ganglia neurons that accompany akinesia and bradykinesia have been supplemented with new knowledge regarding specific pathophysiologic changes that are associated with other parkinsonian signs, such as tremor and gait impairments. New research also emphasizes the role of non-basal ganglia structures in parkinsonism, including the pedunculopontine nucleus, the cerebellum, and the cerebral cortex, and the role of structural and functional neuroplasticity. A more detailed understanding of the brain network abnormalities that result from Parkinson's disease is necessary to arrive at more effective and specific treatments for these symptoms in parkinsonian patients through circuit interventions reaching from deep brain stimulation to genetic and chemogenetic treatments.

The term "basal ganglia" refers to a group of interconnected subcortical nuclei engaged in motor planning and movement initiation, executive functions, behaviors, and emotions. Dopamine released from the substantia nigra is the underlying driving force keeping the basal ganglia network under proper equilibrium and, indeed, reduction of dopamine levels triggers basal ganglia dysfunction, setting the groundwork for several movement disorders. The canonical basal ganglia model has been instrumental for most of our current understanding of the normal and pathological functioning of this subcortical network. This model explains how cortical information flows through the basal ganglia nuclei back to the cortex by going through two pathways with opposing effects that together lead to the proper execution of a given movement. The basal ganglia model has paved the way for the standard clinical management of Parkinson's disease, where pharmacological and neurosurgical treatments in place collectively afford an impressive symptomatic alleviation. Although much of the model has remained, the canonical model has been enriched with new arrivals gathered from evidence provided in the last three decades. Here, we sought to provide a comprehensive review of the basal ganglia network, with emphasis on structure, connectivity patterns, and basic operational principles, both in normal and pathological conditions.

Rare monogenic forms of disease provide a unique opportunity to understand novel pathways in human biology. With the rapid advances in genomics and next-generation sequencing, we now have the tools to interrogate the genomes of patients on a large scale to identify candidate genes in patients with rare monogenic forms of type 1 diabetes (T1D). These cases are more likely to represent genetic defects in critical pathways of immune tolerance, and the study of these patients provides a high-yield pool in which to discover new mechanisms of disease in T1D. These studies are also expected to have high translational impact for the T1D community by helping to identify at-risk individuals and provide compelling candidate targets for prevention and treatment.

Inherited retinal diseases (IRDs) are the leading cause of blindness in working-age individuals worldwide. Their genetic etiology is especially heterogenous, so the development of gene-specific therapies is unlikely to meet the medical needs of the entire patient community. Considering these challenges, a complementary strategy could be to develop therapies independent of the underlying gene variant causing retinal degeneration. As the retina is a neural tissue, it is in theory amenable to neuroprotective therapies that could help prolong cell survival or promote retinal function. Many neurotrophic factors have shown favorable results in preclinical animal models of neurodegenerative diseases, but unfortunately these findings have not yet translated into successful human clinical trials. The clinical development of these new therapies is mostly impeded by selection of pertinent clinical end points and time-to-readout, as the majority of IRDs show a relatively slow disease progression rate. Despite these challenges, several strategies have moved forward into clinical development.