In Krabbe disease, a mutation in GALC gene causes widespread demyelination determining cell death by apoptosis, mainly in oligodendrocytes and Schwann cells. Less is known on the molecular mechanisms induced by this deficiency. Here, we report an impairment in protein synthesis and degradation and in proteasomal clearance with a potential accumulation of the misfolded proteins and induction of the endoplasmic reticulum stress in the brain of 6-day-old twitcher mice (TM) (model of Krabbe disease). In particular, an imbalance of the immunoproteasome function was highlighted, useful for shaping adaptive immune response by neurological cells. Moreover, our data show an involvement of cytoskeleton remodeling in Krabbe pathogenesis, with a lamin meshwork disaggregation in twitcher oligodendrocytes in 6-day-old TM. This study provides interesting protein targets and mechanistic insight on the early onset of Krabbe disease that may be promising options to be tested in combination with currently available therapies to rescue Krabbe phenotype.
Despite the wide range of applications of mRNA therapies, major difficulties exist in the efficient delivery of mRNA into oligodendrocytes, a type of glial cell in the brain. Commonly used viral vectors are not efficient in transforming oligodendrocytes. In this study, we introduced mRNAs into oligodendrocytes with high efficiency and specificity using LUNAR lipid nanoparticles.
Departments of Biochemistry and Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, United States of America.
- Krabbe disease (Kd) is caused by a deficiency in the enzyme GALC, leading to the accumulation of the lipid galactosylceramide (GalCer), which produces a toxic lipid called psychosine that damages myelinating cells and leads to demyelination.
- Research using induced pluripotent stem cells (iPSCs) from Kd patients revealed that Kd myelinating organoids exhibit early myelination defects without affecting other cell types, while the microglia in these organoids show changes in response to GalCer feeding.
- The findings suggest that while Kd model organoids don't show classic lysosomal dysfunction, they provide an essential platform for studying the mechanisms behind demyel
Background: Multimorbidity is linked to poor quality of life, and increased healthcare costs, and multimorbidity risk is potentially mitigated by a healthy lifestyle. This study evaluated the individual and joint contributions of an extensive set of lifestyle factors to the development of multimorbidity.
Methods: A prospective study of 133,719 adults (age 45.
Leukodystrophies represent a heterogeneous group of disorders characterized by specific genetic mutations, metabolic abnormalities, and degeneration of white matter in the central nervous system. These disorders are classified into several categories, with X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (GLD) being the most prevalent demyelinating leukodystrophies in pediatric populations. Maintaining proteostasis, which is critical for normal cellular function, relies fundamentally on the ubiquitin-proteasome system (UPS) and autophagy for the degradation of misfolded and damaged proteins.
Background: Obesity is a risk factor for diabetes mellitus, which commonly coexists with pancreatitis in cats. However, obesity has not previously been associated with pancreatitis in cats.
Objectives: To evaluate factors affecting serum concentrations of pancreatic lipase immunoreactivity (fPLI), trypsin-like immunoreactivity (fTLI), cobalamin and folate in clinically healthy lean, overweight and obese, or diabetic cats.
