Biology subjects

Finkelstein, D. I.

Publications and source records attributed to Finkelstein, D. I..

4 recordsLinked to original sources

bioRxiv2025

Astrocytic FABP5 drives non-cell-autonomous oligodendrocyte injury in multiple system atrophy by promoting TNF signaling and ferroptotic stress

Multiple system atrophy (MSA) is a fatal -synucleinopathy characterized by progressive parkinsonism, cerebellar and autonomic dysfunction. Currently, the mechanisms driving cerebellar white matter neuroinflammation and degeneration in MSA are poorly understood. Here, we identified fatty acid-binding protein 5 (FABP5) as a key factor regulating cerebellar inflammation in MSA pathogenesis in a detailed study of human, mouse and cultured astrocytes. Firstly, transcriptomic profiling of human MSA cerebellar white matter revealed activation of pro-inflammatory and ferroptotic pathways, with FABP5 identified as a key pathway component that is upregulated. We confirmed that FABP5 is upregulated in reactive astrocytes in the PLP--syn transgenic mouse model, also in LPS-treated primary astrocytes. Fabp5 silencing suppressed TNF signaling, mitigated ferroptosis, and restored mitochondrial function. These findings suggest astrocytic FABP5 as a central intracellular regulator linking glial inflammation, ferroptosis, and mitochondrial injury. Overall, this mechanism suggests that FABP5 drives pathology mediated by astrocytes oligodendroglia in MSA, therefore representing a novel and promising therapeutic target.

neuroscience↗

bioRxiv2025

Transgenic A53T mice have astrocytic α-synuclein aggregates in dopamine and striatal regions

AimsParkinsons disease is considered biologically a neuronal -synuclein disease, largely ignoring the more widespread -synuclein deposition that occurs in astrocytes, with the aim of this study to identify whether astrocytes accumulate small -synuclein aggregates before or after neurons. MethodsFixed serial midbrain and striatal sections from M83 A53T transgenic mouse model of Parkinsons disease and wild-type controls were histologically processed for multiplex labelling of -synuclein and astrocytic markers and astrocyte quantitation performed on digital images using QuPath software. ResultsThe density of astrocytes within the substantia nigra pars compacta was approximately 30% greater compared with other sampled regions (P<0.005). Small aggregates of -synuclein were observed in astrocytic processes, including in wild-type mice where a quarter of all astrocytes had an obvious -synuclein aggregate. Compared to wild-type, A53T transgenic astrocytes had significantly enlarged somas (P<0.001) with more processes (P<0.001) consistent with a reactive phenotype. The A53T transgenic mice had more than double the numbers of astrocytes (P<0.001) and 2.5 times more astrocytes with -synuclein aggregates compared to wild-type mice (P<0.001). ConclusionsThese data suggest that small -synuclein aggregates are normally cleared by astrocytes and that the substantia nigra pars compacta requires more astrocytic support for this function than other midbrain dopaminergic regions or the striatum. This adds another vulnerability factor to those already known for the substantia nigra with early deficits in clearance of small -synuclein aggregates by astrocytes associated with an increased astrocytic reactivity in the A53T transgenic mouse model. Key PointsO_LIThe substantia nigra pars compacta contains a higher density of astrocytes than the ventral tegmental area or striatum, indicating a greater reliance on astrocytic function and a greater vulnerability to astrocyte dysfunction C_LIO_LISmall aggregates of -synuclein were observed in wild-type midbrain and striatal astrocytes, indicating normal clearance of -synuclein by these astrocytes C_LIO_LIMidbrain and striatal astrocytes from A53T transgenic astrocytes have more than double the number of astrocytes and more astrocytes containing -synuclein aggregates which have a reactive morphological phenotype. C_LI

neuroscience↗

bioRxiv2022

Epsin2, a novel target for multiple system atrophy therapy via regulating α-synuclein propagation associated with FABP7

Multiple system atrophy (MSA) is a neurodegenerative disease showing accumulation of misfolded -synuclein and myelin disruption. However, the mechanism how -synuclein (-syn) accumulate in MSA brain remains unclear. Here, we identify the protein epsin-2 as a novel target for MSA therapy via controlling -synuclein accumulation. In MSA mouse model, PLP-hSyn transgenic mice and FABP7/-syn hetero-aggregates injected mice, we firstly found that fatty acid-binding protein 7 (FABP7) related to MSA development and formed hetero-aggregates with -syn, which exhibited stronger toxicity than -syn aggregates. Furthermore, injected FABP7/-syn hetero-aggregates in mice selectively accumulated in oligodendrocytes and Purkinje neurons and cause cerebellar dysfunction. By bioinformatic analyses, the protein epsin-2 expresses in both oligodendrocyte and Purkinje cells was found as a potential target to regulate FABP7/-syn hetero-aggregates propagation via clathrin-dependent endocytosis. The AAV5-dependent epsin-2 knock-down mice exhibited decreased levels of aggregates accumulation in Purkinje neurons and oligodendrocytes as well as performed improved myelin levels and Purkinje neurons in cerebellum and motor functions. Thus, we propose epsin-2 as a novel and therapeutic candidate for MSA.

pathology↗

bioRxiv2020

SNCAE46K transgenic Drosophila Model of Parkinsons Disease Confirmed the Causative Role of Oxidative Stress

Parkinsons disease (PD) is a class of neurodegenerative disorders in which, complex interactions of genetic and environmental agents are involved in the etiology of both sporadic and familial PD cases. -synuclein-encoding SNCA gene is known as one of the major genetic contributors of this disease. E46K mutation in SNCA gene has not been investigated as intensive as other SNCA gene mutations including A30P and A53T. In this study, to induce PD in Drosophila flies, UAS-hSNCAWT and UAS-hSNCAE46K transgenic fly lines were constructed, where SNCA gene was over-expressed in flies brains using GAL4-UAS genetic system. Western blot analysis of head samples of SNCA-expressing flies verified SNCA expression at protein level. Light and electron microscopy analysis of ommatidial structures were performed to verify neurodegeneration as a result of -synuclein gene overexpression in Drosophila transgenic flies. Confocal microscopy analysis of dopaminergic neuron clusters verified cell loss following SNCAE46K expression in the flies brain. E46K -synuclein gene over-expression resulted in an evident decline in longevity as well as climbing ability of the flies. Biochemical studies of transgenic flies showed a remarkable decline in antioxidant enzymes activity and a significant increase in oxidative markers level as well as AchE enzyme activity. Oxidative stress has been known as a causal factor in PD pathogenesis, following expression of E46K mutant version of human SNCA gene. This Drosophila model is able to facilitate comparative studies of both molecular and cellular assays implicated in the assessment of neurotoxicity of different -synuclein mutations.

neuroscience↗