Research progress of GBA1 variation and Parkinson′s disease / 中华神经科杂志

GBA1 is one of the common risk genes of Parkinson′s disease (PD), which encodes glucocerebrosidase. It is difficult to distinguish PD patients with heterozygous variants of GBA1 ( GBA1-PD) from idiopathic Parkinson′s disease patients, but GBA1-PD tends to progress faster, be more severe, and be more likely to be associated with cognitive impairment and other non-motor symptoms. The pathological mechanism of the increased risk of PD in GBA1 heterozygous variant carriers may be related to autophagy-lysosome dysfunction and mitochondrial dysfunction. Targeted therapy for GBA1 is expected to become a new direction of precision therapy for PD. In this article, the epidemiology and clinical features of GBA1-PD, the possible pathogenesis of GBA1 variation, and the therapeutic strategies for GBA1-PD were elaborated.

Single-nucleus transcriptomic landscape of primate hippocampal aging

The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

Clinical diagnosis and treatment of non-motor symptoms of multiple system atrophy / 中华神经科杂志

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease with insidious onset, and relatively rapid progress in adult. MSA patients may be admitted to different departments of hospital several years before the full manifestation of motor symptoms, because of various non-motor symptoms such as urinary disorders, sexual dysfunction, orthostatic hypotension, psychic symptoms and sleep disorders. This may delay the diagnosis and treatment of MSA. The review is to improve the understanding of the non-motor symptoms of MSA, which may help to reach more accurate diagnosis and better treatment, and improve the quality of life of patients with MSA.

Chemical screen identifies a geroprotective role of quercetin in premature aging

Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.

Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.

CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells

Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-κB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-κB regulates human blood vessel homeostasis remains largely elusive. Here, using CRISPR/Cas9-mediated gene editing, we generated RelA knockout human embryonic stem cells (hESCs) and differentiated them into various vascular cell derivatives to study how NF-κB modulates human vascular cells under basal and inflammatory conditions. Multi-dimensional phenotypic assessments and transcriptomic analyses revealed that RelA deficiency affected vascular cells via modulating inflammation, survival, vasculogenesis, cell differentiation and extracellular matrix organization in a cell type-specific manner under basal condition, and that RelA protected vascular cells against apoptosis and modulated vascular inflammatory response upon tumor necrosis factor α (TNFα) stimulation. Lastly, further evaluation of gene expression patterns in IκBα knockout vascular cells demonstrated that IκBα acted largely independent of RelA signaling. Taken together, our data reveal a protective role of NF-κB/RelA in modulating human blood vessel homeostasis and map the human vascular transcriptomic landscapes for the discovery of novel therapeutic targets.

Parkinson's Disease with Fatigue: Clinical Characteristics and Potential Mechanisms Relevant to α-Synuclein Oligomer

BACKGROUND AND PURPOSE: The aim of this study was to identify the clinical characteristics and potential mechanisms relevant to pathological proteins in Parkinson's disease (PD) patients who experience fatigue. METHODS: PD patients (n=102) were evaluated using a fatigue severity scale and scales for motor and nonmotor symptoms. The levels of three pathological proteins-α-synuclein oligomer, β-amyloid (Aβ)(1-42), and tau-were measured in 102 cerebrospinal fluid (CSF) samples from these PD patients. Linear regression analyses were performed between fatigue score and the CSF levels of the above-listed pathological proteins in PD patients. RESULTS: The frequency of fatigue in the PD patients was 62.75%. The fatigue group had worse motor symptoms and anxiety, depression, and autonomic dysfunction. The CSF level of α-synuclein oligomer was higher and that of Aβ1-42 was lower in the fatigue group than in the non-fatigue group. In multiple linear regression analyses, fatigue severity was significantly and positively correlated with the α-synuclein oligomer level in the CSF of PD patients, after adjusting for confounders. CONCLUSIONS: PD patients experience a high frequency of fatigue. PD patients with fatigue have worse motor and part nonmotor symptoms. Fatigue in PD patients is associated with an increased α-synuclein oligomer level in the CSF.

Serum uric acid and lifestyle factors associated with the risk of Parkinson's disease / 中华神经科杂志

Objective To investigate the relationship between serum uric acid (UA)levels and Parkinson's disease (PD) risk under specific lifestyle exposures.Methods Case-control study was used.Three hundred and ninety-seven PD cases and the same number of controls with matched age and gender were selected.Demographic and exposure information was collected by face-to-face interview,and blood biochemistry studies tested.Logistic regression model was used to analyze the association of PD risk with UA levels or enviromental factors.Results The highest value of UA levels was associated with a decreased PD risk compared to the lowest value (OR =0.39,95％ CI 0.25-0.63) in both male and female groups.This association was significant among nonsmokers (OR =0.52,95％ CI 0.32-0.76),nondrinkers (OR =0.4,95％ CI 0.34-0.70),and persons taking exercise more than 1 houre a day (OR =0.51,95％ CI 0.35-0.74).But no significant association was affected in the subjects with smoking or drinking history and those with less exercise (＜ 1 hour a day).Conclusion We confirmed that higher UA levels were associated with lower PD risk in Chinese population,and some lifestyles may modify the protection effect of serum UA.

Olfactory function in patients with Parkinsons disease / 中华神经科杂志

Objective To study the olfactory function in Chinese patients with Parkinsons disease (PD) and its application in diagnosis and differential diagnosis of Parkinsonism Methods The thresholds of olfactory detection and identification were determined by using “five odors olfactory detection arrays” provided by Chinese Academy of Sciences for the 50 PD patients, 30 healthy controls, 30 persons with other neurological diseases, and 7 atypical Parkinsons disease patients Results The olfactory detection and identification thresholds of PD patients were significantly higher than those of the normal controls and than those with other neurological diseases But the olfactory identification threshold of PD patients was significantly higher than those with atypical Parkinsons disease The sensitivity and specificity in the olfactory test were 74 0% and 91 7%, respectively by combining the olfactory detection and identification thresholds together Conclusions The olfactory function was found significantly decreased in PD patients The olfactory test might play an important role in the diagnosis and differentiated diagnosis of PD