SNCA and TPPP transcripts increase in oligodendroglial cytoplasmic inclusions in multiple system atrophy.

Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of α-syn accumulation in GCIs is unclear, in particular whether abnormal α-syn aggregates result from the abnormal elevation of endogenous α-syn expression in MSA or ingested from the neuronal source. Tubulin polymerization promoting protein (TPPP) has been reported to play a crucial role in developing GCI pathology. Here, the total cell body, nucleus, and cytoplasmic area density of SNCA and TPPP transcripts in neurons and oligodendrocytes with and without various α-syn pathologies in the pontine base in autopsy cases of MSA (n = 4) and controls (n = 2) were evaluated using RNAscope with immunofluorescence. Single-nucleus RNA-sequencing data for TPPP was evaluated using control frontal cortex (n = 3). SNCA and TPPP transcripts were present in the nucleus and cytoplasm of oligodendrocytes in both controls and diseased, with higher area density in GCIs and glial nuclear inclusions in MSA. Area densities of SNCA and TPPP transcripts were lower in neurons showing cytoplasmic inclusions in MSA. Indeed, TPPP transcripts were unexpectedly found in neurons, while the anti-TPPP antibody failed to detect immunoreactivity. Single-nucleus RNA-sequencing revealed significant TPPP transcript expression predominantly in oligodendrocytes, but also in excitatory and inhibitory neurons. This study addressed the unclear origin of accumulated α-syn in GCIs, proposing that the elevation of SNCA transcripts may supply templates for misfolded α-syn. In addition, the parallel behavior of TPPP and SNCA transcripts in GCI development highlights their potential synergistic contribution to inclusion formation. In conclusion, this study advances our understanding of MSA pathogenesis, offers insights into the dynamics of SNCA and TPPP transcripts in inclusion formation, and proposes regulating their transcripts for future molecular therapy to MSA.

Neuronal SNCA transcription during Lewy body formation.

Misfolded α-synuclein (α-syn) is believed to contribute to neurodegeneration in Lewy body disease (LBD) based on considerable evidence including a gene-dosage effect observed in relation to point mutations and multiplication of SNCA in familial Parkinson's disease. A contradictory concept proposes early loss of the physiological α-syn as the major driver of neurodegeneration. There is a paucity of data on SNCA transcripts in various α-syn immunoreactive cytopathologies. Here, the total cell body, nuclear, and cytoplasmic area density of SNCA transcripts in neurons without and with various α-syn immunoreactive cytopathologies in the substantia nigra and amygdala in autopsy cases of LBD (n = 5) were evaluated using RNAscope combined with immunofluorescence for disease-associated α-syn. Single-nucleus RNA sequencing was performed to elucidate cell-type specific SNCA expression in non-diseased frontal cortex (n = 3). SNCA transcripts were observed in the neuronal nucleus and cytoplasm in neurons without α-syn, those containing punctate α-syn immunoreactivity, irregular-shaped compact inclusion, and brainstem-type and cortical-type LBs. However, SNCA transcripts were only rarely found in the α-syn immunoreactive LB areas. The total cell body SNCA transcript area densities in neurons with punctate α-syn immunoreactivity were preserved but were significantly reduced in neurons with compact α-syn inclusions both in the substantia nigra and amygdala. This reduction was also observed in the cytoplasm but not in the nucleus. Only single SNCA transcripts were detected in astrocytes with or without disease-associated α-syn immunoreactivity in the amygdala. Single-nucleus RNA sequencing revealed that excitatory and inhibitory neurons, oligodendrocyte progenitor cells, oligodendrocytes, and homeostatic microglia expressed SNCA transcripts, while expression was largely absent in astrocytes and microglia. The preserved cellular SNCA expression in the more abundant non-Lewy body type α-syn cytopathologies might provide a pool for local protein production that can aggregate and serve as a seed for misfolded α-syn. Successful segregation of disease-associated α-syn is associated with the exhaustion of SNCA production in the terminal cytopathology, the Lewy body. Our observations inform therapy development focusing on targeting SNCA transcription in LBD.

G-jitter induced magnetohydrodynamics flow of nanofluid with constant convective thermal and solutal boundary conditions.

Taking into account the effect of constant convective thermal and mass boundary conditions, we present numerical solution of the 2-D laminar g-jitter mixed convective boundary layer flow of water-based nanofluids. The governing transport equations are converted into non-similar equations using suitable transformations, before being solved numerically by an implicit finite difference method with quasi-linearization technique. The skin friction decreases with time, buoyancy ratio, and thermophoresis parameters while it increases with frequency, mixed convection and Brownian motion parameters. Heat transfer rate decreases with time, Brownian motion, thermophoresis and diffusion-convection parameters while it increases with the Reynolds number, frequency, mixed convection, buoyancy ratio and conduction-convection parameters. Mass transfer rate decreases with time, frequency, thermophoresis, conduction-convection parameters while it increases with mixed convection, buoyancy ratio, diffusion-convection and Brownian motion parameters. To the best of our knowledge, this is the first paper on this topic and hence the results are new. We believe that the results will be useful in designing and operating thermal fluids systems for space materials processing. Special cases of the results have been compared with published results and an excellent agreement is found.

Double diffusive magnetohydrodynamic (MHD) mixed convective slip flow along a radiating moving vertical flat plate with convective boundary condition.

In this study combined heat and mass transfer by mixed convective flow along a moving vertical flat plate with hydrodynamic slip and thermal convective boundary condition is investigated. Using similarity variables, the governing nonlinear partial differential equations are converted into a system of coupled nonlinear ordinary differential equations. The transformed equations are then solved using a semi-numerical/analytical method called the differential transform method and results are compared with numerical results. Close agreement is found between the present method and the numerical method. Effects of the controlling parameters, including convective heat transfer, magnetic field, buoyancy ratio, hydrodynamic slip, mixed convective, Prandtl number and Schmidt number are investigated on the dimensionless velocity, temperature and concentration profiles. In addition effects of different parameters on the skin friction factor, [Formula: see text], local Nusselt number, [Formula: see text], and local Sherwood number [Formula: see text] are shown and explained through tables.

g-Jitter mixed convective slip flow of nanofluid past a permeable stretching sheet embedded in a Darcian porous media with variable viscosity.

The unsteady two-dimensional laminar g-Jitter mixed convective boundary layer flow of Cu-water and Al2O3-water nanofluids past a permeable stretching sheet in a Darcian porous is studied by using an implicit finite difference numerical method with quasi-linearization technique. It is assumed that the plate is subjected to velocity and thermal slip boundary conditions. We have considered temperature dependent viscosity. The governing boundary layer equations are converted into non-similar equations using suitable transformations, before being solved numerically. The transport equations have been shown to be controlled by a number of parameters including viscosity parameter, Darcy number, nanoparticle volume fraction, Prandtl number, velocity slip, thermal slip, suction/injection and mixed convection parameters. The dimensionless velocity and temperature profiles as well as friction factor and heat transfer rates are presented graphically and discussed. It is found that the velocity reduces with velocity slip parameter for both nanofluids for fluid with both constant and variable properties. It is further found that the skin friction decreases with both Darcy number and momentum slip parameter while it increases with viscosity variation parameter. The surface temperature increases as the dimensionless time increases for both nanofluids. Nusselt numbers increase with mixed convection parameter and Darcy numbers and decreases with the momentum slip. Excellent agreement is found between the numerical results of the present paper with published results.

MHD free convective boundary layer flow of a nanofluid past a flat vertical plate with Newtonian heating boundary condition.

Steady two dimensional MHD laminar free convective boundary layer flows of an electrically conducting Newtonian nanofluid over a solid stationary vertical plate in a quiescent fluid taking into account the Newtonian heating boundary condition is investigated numerically. A magnetic field can be used to control the motion of an electrically conducting fluid in micro/nano scale systems used for transportation of fluid. The transport equations along with the boundary conditions are first converted into dimensionless form and then using linear group of transformations, the similarity governing equations are developed. The transformed equations are solved numerically using the Runge-Kutta-Fehlberg fourth-fifth order method with shooting technique. The effects of different controlling parameters, namely, Lewis number, Prandtl number, buoyancy ratio, thermophoresis, Brownian motion, magnetic field and Newtonian heating on the flow and heat transfer are investigated. The numerical results for the dimensionless axial velocity, temperature and nanoparticle volume fraction as well as the reduced Nusselt and Sherwood number have been presented graphically and discussed. It is found that the rate of heat and mass transfer increase as Newtonian heating parameter increases. The dimensionless velocity and temperature distributions increase with the increase of Newtonian heating parameter. The results of the reduced heat transfer rate is compared for convective heating boundary condition and found an excellent agreement.