Biology subjects

Guttman, L.

Publications and source records attributed to Guttman, L..

3 recordsLinked to original sources

bioRxiv2025

Screening of a kinase library in human Huntington disease iPSC derived striatal precursor neurons reveals a neuroprotective effect of PKC alpha and PKC beta1 inhibition

The loss of striatal medium spiny neurons is a hallmark of Huntingtons disease (HD). To identify potential disease-modifying treatments, we previously developed a human neuronal model by immortalizing and differentiating HD patient-derived iPSCs into highly homogeneous striatal precursor neurons (ISPNs). Using a 96-well screening platform, and two rounds of re-screening, we tested a kinase inhibitor library and identified 5 compounds that protected HD ISPNs from mutant huntingtin (mHTT)-induced toxicity. Among these, we prioritized the PKC-/{beta}1 inhibitor GO6976, which rescued HD ISPNs from mHTT toxicity in a dose-dependent manner. Further, we found increased phosphorylation of PKC- and PKC-{beta}1 in HD cells and tissues, while their overexpression was toxic to HD ISPNs. Knockdown of PKC-/{beta}1 protected the neurons, and both isoforms interacted and colocalized with HTT. These results suggest that PKC-/{beta}1 plays a role in HD neurodegeneration, and that inhibiting their activity may offer a potential therapeutic approach for HD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/677178v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@256d6org.highwire.dtl.DTLVardef@1931e7borg.highwire.dtl.DTLVardef@1b6598borg.highwire.dtl.DTLVardef@b0bbb5_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHD patient-derived iPSC-based striatal precursor neurons (ISPNs) were used to screen and identify neuroprotective compounds. C_LIO_LIThe PKC-/{beta}1 inhibitor GO6976 rescues HD ISPNs from mutant huntingtin (HTT)-induced toxicity. C_LIO_LIThe phosphorylation of PKC-/{beta}1 is elevated in HD cell and tissues, and PKC-/{beta}1 interact with both wild-type and mutant huntingtin. C_LIO_LIOverexpression of PKC-/{beta}1 is toxic to HD ISPNs, while its knockdown protects the neurons. C_LI

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↗

bioRxiv2021

The anterior insular cortex associates temporally discontiguous stimuli during threat learning

Learning about potential threats in the environment is indispensable for survival. Deficits in threat learning constitute a key dimension of multiple brain disorders, which include posttraumatic stress disorder and anxiety disorder. While human brain imaging studies have highlighted a reliable engagement of the anterior insular cortex (AIC) in threat learning, its precise role remains elusive partly due to the lack of animal studies that can address causality and mechanistic questions. Filling in this gap, the present mouse study proposes a novel AIC-mediated mechanism underlying the association of temporally discontiguous stimuli during threat learning. We identified that activity of AIC layer 5 (L5) pyramidal neurons is required for associating temporally discontiguous stimuli, specifically during a time interval between them. Notably, the AIC is not required for associating temporally contiguous stimuli during threat learning. The AIC not only sends the essential information, via its L5 pyramidal neurons, to the basolateral amygdala (BLA) during the time interval, but also receives from the BLA. We also identified a modulatory role of AIC dopamine D1 receptor (D1R)-mediated dopamine signaling in associating temporally discontiguous stimuli during the time interval.

neuroscience↗