Changes in the level of metabolites, small molecules that are intermediates produced by metabolism or catabolism, are associated with developing diseases. Metabolite signatures in body fluids such as plasma, cerebrospinal fluid, urine, and saliva are associated with Parkinson’s disease. Here, we discuss alteration of metabolites in the TCA cycle, pentose phosphate pathway, kynurenic network, and redox system. We also summarize the efforts of many research groups to differentiate between metabolite profiles that characterize PD motor progression and dyskinesia, gait and balance, and non-motor symptoms such as depression and cognitive decline. Understanding how changes in metabolites lead to progression in PD may allow for the identification of individuals at the earliest stage of the disease and the development of new therapeutic strategies.

In this study, we describe a role for the mammalian Numb-interacting protein 1 (Nip1) in regulation of neuronal differentiation in stem cells. The expression of Nip1 was detected in the developing mouse brain, embryonic stem cells, primary neuronal stem cells, and retinoic acid-treated P19 embryonal carcinoma cells. The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production. Ectopic nip1 expression in P19 embryonal carcinoma cells induced neuronal differentiation, and this phenotype was also linked to elevated ROS production. The neuronal differentiation in nip1-overexpressing P19 cells was achieved in a retinoic acid-independent manner and was corroborated by an increase in the expression of the neuronal basic helix-loop-helix transcription factors and neural-lineage cell markers. Furthermore, depletion of nip1 by short hairpin RNA led to a decrease in the expression of neuronal basic helix-loop-helix transcription factors and ROS. However, inhibition of ROS production in nip1-overexpressing P19 cells restricted but did not extinguish neuronal differentiation. Microarray and mass spectrometry analysis identified intermediate filaments as the principal cytoskeletal elements affected by up-regulation of nip1. We show here the first evidence for a functional interaction between Nip1 and a component of the nuclear lamina, lamin A/C. associated with a neuronal-specific phenotype. Taken together, our data reveal an important role for Nip1 in the guidance of neuronal differentiation through ROS generation and modulation of intermediate filaments and implicate Nip1 as a novel intrinsic regulator of neuronal cell fate.

Parkinson disease (PD) and essential tremor (ET) are two common adult-onset tremor disorders in which prevalence increases with age. PD is a neurodegenerative condition with progressive disability. In ET, neurodegeneration is not an established etiology. We sought to determine whether an underlying metabolic pattern may differentiate ET from PD. Circulating metabolites in plasma and cerebrospinal fluid were analyzed using gas chromatography-mass spectroscopy. There were several disrupted pathways in PD compared to ET plasma including glycolysis, tyrosine, phenylalanine, tyrosine biosynthesis, purine and glutathione metabolism. Elevated α-synuclein levels in plasma and CSF distinguished PD from ET. The perturbed metabolic state in PD was associated with imbalance in the pentose phosphate pathway, deficits in energy production, and change in NADPH, NADH and nicotinamide phosphoribosyltransferase levels. This work demonstrates significant metabolic differences in plasma and CSF of PD and ET patients.