Alzheimer & Parkinson

Selective endoplasmic reticulum (ER) macroautophagy/autophagy, also called reticulophagy, is a disposal pathway that degrades ER domains. A major role of reticulophagy is the removal of ER domains that contain misfolded proteins resistant to ER-associated degradation (ERAD). Our studies have shown that RTN3L, the SEC24C-SEC23 COPII coat subcomplex, and the CUL3^(KLHL12) E3 ligase that ubiquitinates RTN3L targets ERAD-resistant misfolded protein condensates for degradation at ER-reticulophagy...

The silkworm Bombyx mori is an economically important insect for silk production. Its silk glands are responsible for the synthesis and secretion of silk proteins. The naked pupa (Nd), a fibroin heavy chain mutant strain of silkworm, was found to exhibit severe atrophy, degeneration of the posterior silk gland (PSG), and abnormal secretion of fibroin proteins, thereby producing little or no silk. Here, we found that the autophagic marker Atg8-PE was upregulated through the target of rapamycin...

Reactive gliosis is a hallmark of neuropathology and offers a potential target for addressing numerous neurological diseases. Here, we show that growth arrest and DNA damage inducible gamma (GADD45G), a stress sensor in astrocytes, is a nodal orchestrator of reactive gliosis and neurodegeneration. GADD45G expression in astrocytes is sufficient to incite astrogliosis, microgliosis, synapse loss, compromised animal behavior, and the aggravation of Alzheimer's disease (AD). Conversely, silencing...

CONCLUSIONS: Our results suggest that combining motor training with tDCS improves motor function, particularly in gait-related parameters, in PD patients. However, these effects were not sustained over time, highlighting the temporary nature of the benefits. Sex differences may influence the acute effects of combined motor training and tDCS interventions.

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for amyloid-β (Aβ) generation and is considered promising drug target for Alzheimer's disease (AD). The co-chaperone BAG3 (Bcl-2-associated athanogene 3) plays an important role in maintaining intracellular protein homeostasis by regulating heat shock protein 70 (HSP70). Here, we reported that BAG3 expression was significantly elevated in AD. It interacted with and stabilized BACE1 by delaying its...

Dysfunction of the glymphatic system, a brain-wide waste clearance network, is strongly linked to Alzheimer's disease (AD) and the accumulation of β-amyloid (Aβ) and tau proteins. Here, we identify an astrocytic signaling pathway that can be targeted to preserve glymphatic function and mitigate neurotoxic protein buildup. Analysis of astrocytes from both human AD brains and two transgenic mouse models (5XFAD and PS19) reveals robust activation of the protein kinase RNA-like endoplasmic reticulum...

The Miro1 protein is a member of the mitochondrial Rho GTPase (Miro) protein family and plays a crucial role in regulating the dynamic processes of mitochondria and participating in cellular movement and mitochondrial transport. In the nervous system, it ensures adequate energy supply for normal neuronal function and synaptic transmission. Additionally, Miro1 actively participates in the regulation of mitochondrial quality control and stress responses within neurons. Its primary function is to...

Alzheimer's disease (AD) is still an excessively complicated neurological disorder that impacts millions of individuals globally. The ideal defensive feature of the central nervous system (CNS) is the intimate junction of endothelial cells, which functions as a biological barrier to safely control molecular transport throughout the brain. The blood-brain barrier (BBB) comprises tightly locked astrocyte cell junctions on CNS blood capillaries. This biological barrier shields the brain from...

Tremor occurs in various forms across diverse neurological disorders, including Parkinson's disease and essential tremor. While clinically heterogeneous, converging evidence suggests a shared brain network may underlie tremor across conditions. Here, we empirically define such a network using four modalities: lesion locations, atrophy patterns, EMG-fMRI, and deep brain stimulation outcomes. We show that network connectivity robustly explains clinical outcomes in independent cohorts undergoing...

Preservation of synapses is crucial for healthy cognitive ageing, and synapse loss is one of the closest anatomical correlates of cognitive decline in Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia. In these conditions, some synapses seem particularly vulnerable to degeneration whereas others are resilient and remain preserved. Evidence has highlighted that vulnerability and resilience are intrinsically distinct phenomena linked to specific brain structural and/or...

Brain endothelial cells (BECs) in brain vasculature are critical structural and functional components of the blood brain barrier (BBB). Adeno-associated virus (AAV) capsids have previously been genetically engineered to confer specificity to endothelial cells, but these capsids show limited endothelial cell specificity that varies by delivery conditions. We developed a set of new BEC-enhancer AAV vectors that specifically target BECs based on the cis-regulatory elements identified from...

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Sexual dysfunction (SD) is a common non-motor symptom in Parkinson's disease (PD) that substantially reduces patients' quality of life. However, the underlying neural mechanisms of SD in PD remain poorly understood. This study aimed to investigate the role of functional abnormalities in brain regions with dopaminergic innervation in male PD patients with SD, using resting-state functional magnetic resonance imaging (rs-fMRI). A total of 34 male PD patients were enrolled. The bilateral caudate,...

The associations of β-amyloid (Aβ) and tau deposition with white matter (WM) degeneration in Alzheimer's disease (AD) remain inadequately elucidated. We investigate baseline and longitudinal changes of microstructural fractional anisotropy (FA) and macrostructural white matter hyperintensities (WMHs) and their relationships with Aβ and tau positron emission tomography (PET) and vascular risk factors in different Aβ/tau stages defined by PET imaging. Lower levels and faster decline rates of FA...

The sense of smell is essential for human perception. Olfactory function declines with increasing age, affecting a substantial portion of the elderly population, and this decline is more pronounced in men. This reduction can be attributed to anatomical and degenerative changes in the brain and olfactory receptors. There is robust clinical evidence indicating an association between olfactory perception decline/deficit (OPD) and major neurodegenerative diseases, with severe deficits observed in...

Alzheimer's disease (AD) and traumatic brain injury (TBI) are currently untreatable neurodegenerative disorders afflicting millions of people worldwide. These conditions are pathologically related, and TBI is one of the greatest risk factors for AD. Although blood-brain barrier (BBB) disruption drives progression of both AD and TBI, strategies to preserve BBB integrity have been hindered by lack of actionable targets. Here, we identify 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme...

Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a...

Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A (CgA) knockout (CgA-KO) mice. CgA is known to be associated with protein aggregates in the brains of neurodegenerative diseases including Alzheimer's disease (AD). Here, we investigated the role of CgA in Tau pathogenesis in AD and corticobasal degeneration (CBD). CgA ablation in Tauopathy mice (PS19) (CgA-KO/PS19)...

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila. We also measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease and identified Alzheimer's genetic variants that modify gene expression in disease-vulnerable neurons in...

Ferritins are ubiquitous proteins that function in iron storage/detoxification by catalyzing the oxidation of Fe^(2+) ions and solubilizing the resulting Fe^(3+)-oxo mineral. Mammalian tissues that are metabolically highly active contain, in addition to the widespread cytosolic ferritin, a ferritin that is localized to mitochondria. Mitochondrial ferritin (FtMt) protects against oxidative stress and is found at higher levels in diseases associated with abnormal iron accumulation, including...