Biology subjects

Kam, T.-I.

Publications and source records attributed to Kam, T.-I..

6 recordsLinked to original sources

bioRxiv2026

Splanchnic-spinal transmission of gut-initiated α-synucleinopathy

Gut-initiated -synucleinopathy is proposed to spread from the gastrointestinal tract to the CNS, contributing to Parkinson's disease (PD), but whether routes beyond the vagus nerve are involved remains unclear. Using complementary intracolonic rotenone and gastroduodenal -synuclein PFF models, we combined pathway-specific surgical interruption with longitudinal behavioral analysis and anatomical mapping of pathological -synuclein. In the intracolonic rotenone model, interruption of the prevertebral ganglia/splanchnic-spinal axis more strongly attenuated behavioral deficits and -synuclein pathology than vagotomy. In the gastroduodenal PFF model, both vagal and splanchnic-spinal pathways contributed to pathology propagation. Early after PFF inoculation, pathological -synuclein was detected in peripheral neural structures associated with both routes. Consistent with these findings, spinal pathology was evident in human PD. Together, these results identify the splanchnic-spinal pathway as a key component of body-first Parkinson's disease, broadening current models of peripheral-to-central disease progression and informing efforts to target early peripheral disease progression.

neuroscience↗

bioRxiv2026

Reactive Astrocytes Drive Extracellular Acidification to Mediate α-Synuclein Neurodegeneration

Astrocytes are increasingly recognized as key players in neurodegeneration1-3, yet the molecular mechanisms by which they drive disease remain elusive. Here, we uncover a fundamental pathway in which reactive astrocytes fuel neurodegeneration in -synucleinopathies--including Dementia with Lewy bodies and Parkinsons disease dementia--by acidifying the brains extracellular environment. We demonstrate that both human patient tissue and a gut-to-brain -synuclein mouse model exhibit accumulation of reactive astrocytes and extracellular acidosis. Mechanistically, we show that astrocytic lysosomal exocytosis releases acidic contents, driving a drop in pH that activates neuronal acid-sensing ion channel 1a (ASIC1a), resulting in neuronal loss and behavioral decline. Blocking this pathway--either by inhibiting astrocytic lysosomal exocytosis or genetically or pharmacologically targeting neuronal ASIC1a--mitigates pathology and rescues neurodegenerative phenotypes in vivo. These findings provide a conceptual advance by establishing a mechanistic link between glial inflammation, acid-base homeostasis, and neuronal vulnerability, and suggest that targeting astrocyte-driven acidification or ASIC1a signaling could offer new avenues for disease modification in -synucleinopathies.

neuroscience↗

bioRxiv2025

Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer Disease Model

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimers disease (AD), yet its role in amyloid-{beta} (A{beta}) pathology remains unclear. Here, we show that PARP1 activation drives A{beta} pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric A{beta}1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein (APP) and BACE1 levels, altered {gamma}-secretase complex composition, and enhanced A{beta} degradation via neprilysin. These findings position PARP1 as a critical mediator of A{beta} toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD. Significance StatementOur study identifies poly(ADP-ribose) (PAR) as an elevated biomarker in the cerebrospinal fluid of patients with mild cognitive impairment and Alzheimers disease, correlating with established markers of amyloid pathology. We demonstrate that PARP1, the enzyme responsible for PAR synthesis, is activated by neurotoxic A{beta}1-42 and mediates neuronal death, amyloid plaque formation, neuroinflammation, and cognitive deficits in a mouse model of AD. Importantly, genetic ablation of PARP1 not only protects neurons from A{beta} toxicity but also reduces amyloid burden by suppressing A{beta} production and enhancing its degradation. These findings highlight PARP1 as a critical regulator of amyloid pathology and neurodegeneration, and suggest that PARP1 inhibition may offer a promising therapeutic avenue for Alzheimers disease by simultaneously targeting multiple pathogenic mechanisms.

neuroscience↗

bioRxiv2023

Histone H1.2 Dependent Translocation of Poly (ADP-ribose) Initiates Parthanatos

Toxic cellular insults activate the nuclear protein poly (ADP-ribose) (PAR) polymerase-1 (PARP-1) to initiate parthanatos, a regulated cell death program. PAR acts as a death signal by translocating from the nucleus to the cytosol, where it activates the next steps in the parthanatic cell death cascade. How PAR translocates from the nucleus to the cytosol is not known. Here we show that PARylation and PAR binding to histone H1.2 enables it to act as a carrier, transporting PAR out of the nucleus to the cytosol. Knocking down the expression of histone H1.2 via CRISPR/Cas9 and knockout of histone H1.2 reduces the translocation of PAR to the cytosol after treatment of human cortical neurons with N-methyl-D-aspartate (NMDA) or following oxygen-glucose deprivation (OGD). The PAR-dependent E3 ubiquitin ligase, Iduna (RNF146) ubiquitinates PARylated H1.2. Overexpression of Iduna reduces the expression levels of cytosolic histone H1.2, preventing the translocation of PAR following NMDA or OGD exposure, similar to inhibition of PAR formation by the PARP inhibitor, DPQ. Whereas, the catalytically null variant Iduna C60A, or the PAR binding mutant Iduna Y156A and R157A (YRAA) was ineffective in ubiquitinating histone H1.2 and preventing the reduction in cytosolic histone H1.2 levels and PAR translocation from the nucleus to the cytosol. Histone H1.2 heterozygote and homozygote knockout mice exhibited reduced infarct volume 24 hrs post middle cerebral artery occlusion (MCAO) and showed better recovery in motor deficits than wildtype littermates at day 3 and/or day 7 post MCAO. Collectively, these findings reveal histone H1.2 as the key carrier of PAR out of the nucleus to the cytosol where it participates in the next step of the parthanatic cell death cascade.

cell biology↗

bioRxiv2022

Poly ADP-Ribose Signaling is Dysregulated in Huntington Disease Patients

Huntington disease (HD) is a genetic neurodegenerative disease caused by CAG expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the huntingtin (HTT) protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly ADP-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD iPSC-derived neurons and patient- derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in huntingtin, detected huntingtin complexed with PARylated proteins in human cells during stress, and localized huntingtin to mitotic chromosomes upon inhibition of PAR degradation. Direct huntingtin PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild type and mutant huntingtin did not differ in their PAR binding ability, purified wild type huntingtin protein increased in vitro PARP1 activity while mutant huntingtin did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies. Significance statementA consensus on dysfunctional DNA repair has emerged in neurodegenerative disease research, with elevated poly ADP-ribose (PAR) signaling more recently implicated. In contrast, we have identified a deficient PAR response in Huntingtons disease (HD) patient spinal fluid samples and cells. This may be explained by the inability of huntingtin protein bearing the HD-causing mutation to stimulate production of PAR the way the wild type protein does. Since drugs that target PAR production and degradation have already been developed, these findings present an exciting avenue for therapeutic intervention for HD.

neuroscience↗

bioRxiv2020

Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in alpha-synuclein-based mouse models of Parkinson's disease

Parkinsons disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and eventually, cognitive impairment. -Synuclein protein has been known to be the most culprit protein, but the underlying pathological mechanism still remains to be elucidated. As an effort to clarify the pathogenesis mechanism by -synuclein, various PD mouse models with -synuclein overexpression have been developed. However, the systemic analysis of protein abundance change by the overexpressed -synuclein in the whole proteome level has been still lacking. To address this issue, we established two sophisticated mouse models of PD by injecting -synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T -synuclein to discover overlapping pathways, which could be altered in the two different types of PD mouse model. For more accurate quantification of mouse brain proteome, stable isotope labeling with amino acid in mammal-based quantification was implemented. As a result, we have successfully identified a total of 8,355 proteins from both of the mouse models; [~]6,800 and [~]7,200 proteins from -synuclein PFF injected mice and human A53T -synuclein transgenic mice, respectively. From the pathway analysis of the differentially expressed proteins in common, the complement and coagulation cascade pathway were determined as the most enriched ones. This is the first study that highlights the significance of the complement and coagulation pathway in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.

neuroscience↗