Alzheimer & Parkinson

Golgi fragmentation is an early and common feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). However, whether a shared mechanism drives Golgi fragmentation across different neurodegenerative conditions remains unclear. Here, we identify the E3 ubiquitin-protein ligase Itchy homolog (ITCH) as a key regulator of proteotoxicity through its role in inducing Golgi fragmentation. Disease-associated accumulation of ITCH promotes...

The acidic pH of lysosomes required for function is established by the electrogenic V-ATPase proton pump. How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson's disease (PD)-associated protein TMEM175 was proposed as a H+-selective channel to leak protons to counter over-acidification. We rigorously address key findings and predictions of this model and show that, in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective...

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly...

In Alzheimer's disease (AD), hyperactivated microglia produce inflammatory mediators that contribute to neuroinflammation and neuronal damage. Amyloid precursor protein (APP), a transmembrane protein expressed in many cell types, including neurons and microglia, plays a critical role in AD pathogenesis via its secretase-mediated processing to release the C-terminal 99-residue transmembrane fragment (C99) that is further cleaved to yield amyloid-β peptides. Voltage-gated proton channels (Hv1)...

Parkinson disease (PD) and other α-synucleinopathies are characterized by the intracellular aggregates of SNCA/α-synuclein (synuclein, alpha) thought to spread via cell-to-cell transmission. To understand the contributions of various brain cells to the spreading of SNCA pathology, we examined the metabolism of SNCA aggregates in neuronal and glial cells. In neurons, while the full-length SNCA rapidly disappeared following SNCA pre-formed-fibril (PFF) uptake, truncated SNCA accumulated with a...

Recent advances in single-cell transcriptomics have led to the identification of disease-associated microglia (DAM) as a distinct, conserved microglia state associated with mouse models of Alzheimer's disease (AD) and amyotrophic lateral sclerosis, and with aging. DAM are characterized by downregulation of homeostatic genes and upregulation of lipid metabolism and phagocytosis genes, including key risk factors for AD in humans. Although characterized in models of AD, whether DAM acts as...

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We previously reported that T96K is a gain-of-function mutation in TREM2 based on its ability to increase ligand-dependent activation. Here, we show that TREM2^(T96K) increases risk for Alzheimer's disease (AD) in a whole-genome sequencing dataset comprised of family-based and case-control samples. Trem2^(T96K) also reduced clustering of microglia around β-amyloid (Aβ) plaques exclusively in female 5xFAD mice. Furthermore, T96K decreased levels of soluble Trem2 in female 5xFAD mice and human...

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are major public health challenges. Current treatments are only symptomatic and do not address the underlying pathogenic genetic mechanisms. The development of the CRISPR/Cas genome editing tool has increased possibilities for targeted repair of pathological mutations. CRISPR/Cas9, Cas12, and Cas13 systems enable targeted editing and transcriptome modulation in various preclinical...

Patient-specific, human-based cellular models integrating a biomimetic blood-brain barrier, immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. To construct a human cell-based model that includes these features and all six major brain cell types needed to mimic disease and dissect pathological mechanisms, we have constructed, characterized, and utilized a multicellular...

Alzheimer's disease is a neurodegenerative disorder with a variable rate of progression. Predictive tools that can leverage the available modalities of data in any setting to predict the progression of the disease will benefit clinicians and patients alike. However, most of the tools lack the ability to quantify the uncertainty and do not provide the reasoning behind the predictions. In this work, we propose a novel Bayesian Encoder-Decoder GRU (BEND-GRU) framework to predict a patient's...

Tau misfolding into β-sheet-rich filaments and subsequent recruitment of monomeric tau are central to Alzheimer's disease (AD) pathogenesis. While cryo-EM has resolved the conformation of the AD tau core, the structural features conferring biological activity remain unclear. Here, we investigated how tau filament core structure and post-translational modifications influence seeding capacity in neurons and mice. Our findings show that although filament structure impacts seeding, the AD tau core...

Neuronal aggregates of Tau are a hallmark of Alzheimer's disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions, while some have co-aggregates of the two proteins. The presence of such co-aggregates is associated with increased disease severity, although whether there is a causal relationship remains unclear. Here, we demonstrate that Tau and TDP-43 mutually promote each other's condensation through direct interaction in vitro, forming irregularly-shaped or...

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APOE4 is the primary risk factor for Alzheimer disease (AD). Early AD pathological events first affect the neuronal endolysosomal system, which in turn causes neuronal protein aggregation and cell death. Despite the crucial influence of lysosomes upon AD pathophysiology, and that APOE4 localizes to lysosomes, the influence of APOE4 on lysosomal function remains unexplored. We find that expression of APOE4 in neuronal cell lines results in lysosomal alkalinization and impaired lysosomal function....

Parkinson's disease (PD) has been associated with alterations in neuronal activity in the basal ganglia-thalamocortical (BGTC) network. Previous studies have suggested that cortical disinhibition is a feature of PD, but there has been little direct evidence of the changes in cortical neuronal spiking activity to support this hypothesis. To test the hypothesis that activity in the motor cortex is enhanced in PD, we investigated the effects of parkinsonism on movement-related neuronal activity in...

Parkinson's disease (PD) is a most common neurodegenerative disorder caused by genetic, epigenetic, and environmental factors. DNA methylation, regulated by DNA methyltransferases (DNMTs) is the key epigenetic modification playing an important role in gene expression regulation. Oligomeric alpha-synuclein - a major neurotoxic agent in PD - could sequester DNMT1 from the cell nucleus to the cytoplasm leading to global DNA hypomethylation. Here we evaluated DNMT1 expression (mRNA, protein),...

Parkinson's disease (PD) is being increasingly recognized for its complex clinical symptoms, including cognitive impairment, which are linked to dynamic changes in brain network configuration and genetic susceptibility. However, the time-varying patterns of network reconfiguration in patients with PD and their relationship with gene expression profiles and cognitive function remain unclear. To address this gap, we analyzed modular variability (MV) in time-varying brain networks-comparing group...

Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD...

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