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TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination.
Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43-mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies-related diseases.
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Ultrastructural study of electrophysiologically identified neurones in the paraventricular nucleus of the rat.
The ultrastructural characterization of electrophysiologically identified neurones of the rat paraventricular hypothalamic nucleus was performed with extracellular labelling technique. The extracellularly recorded neurons are labelled with an electrophoretic deposit of alcian blue contained in the recording micropipette. The neurone thus labelled takes on a dark and shrunken appearance which enables its detection among neighbouring cells without, however, concealing its main morphological characteristics. 1) Spontaneously firing neurones, invaded by an antidromic action potential elicited by electrical stimulation of the neurohypophysis, were identified as magnocellular cells containing dense-cored vesicles of 200-250 nm in diameter. Dense-cored vesicles were not found in the antidromically activated neurones devoid of spontaneous activity. 2) Trans-synaptically activated neurones in the PVN or in its dorso-lateral edge were small cells devoid of dense secretory vesicles. 3) PV neurones in which neurohypophysial stimulation evoked no response, contained small, dense vesicles (100 nm in diameter) comparable with those found in parvocellular peptidergic neurones.
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Ultrastructural organization of actin filaments in neurosecretory axons of the rat.
The ultrastructural organization of actin filaments was studied in the neurohypophysial system of the rat after heavy meromyosin (HMM) labeling. This structural pattern is characterized by (1) a straight arrangement of the filaments parallel to the axonal axis in the proximal nondilated parts of axons, (2) a central location within axonal dilatations, and (3) a higher concentration within axonal endings where the filaments form a complex three-dimensional network. The relationships of the filaments to other axonal structures and organelles was further studied by use of electron microscopic stereoscopy. The actin filaments frequently appear anchored to the axolemma with either polar arrangements of the arrowhead decoration (i) at structurally undifferentiated sites, and (ii) more particularly within perivascular endings, at sites with electron-dense thickenings. In all axonal divisions actin filaments are also found to bind to filamentous material surrounding the microtubules and to various organelles. Within the terminal portions of the axons actin filaments exhibit close relationships to neurosecretory granules and to the numerous smooth microvesicles found in this region. Such preferential relationships are particularly observed both in axon ;terminals and in pituicytes, with coated vesicles frequently binding actin filaments. In water-deprived rats, the concentration of actin filaments is conspicuously increased along the axons and more clearly in the axonal swellings and endings, where they form a more complex and interconnected network. These data are discussed in the light of a possible involvement of contractile proteins in the mechanisms of axonal transport and terminal release of neurosecretory products.
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Synaptic relationships between a multipolar stellate cell and a pyramidal neuron in the rat visual cortex. A combined Golgi-electron microscope study.
Two synapsing and impregnated neurons in the rat visual cortex have been examined by a combined Golgi-electron microscope technique in which the Golgi precipitate is replaced by gold particles. One of the neurons is a stellate cell with smooth dendrites and a well impregnated axon, while the other is a layer III pyramidal neuron. Light microscopy showed some boutons from the axonal plexus of the stellate cell closely apposed to the soma and dendrites of the pyramid and it was predicted that synapses were present at these sites. An electron microscopic examination of serial thin sections, in which the profiles of the impregnated neurons are marked by their content of gold particles, showed most of these predicted synapses to exist. Indeed, axon terminals of the stellate cell formed five symmetric synapses with the cell body of the pyramid, one with the apical dendritic shaft and three with basal dendrites. Reasons are given for believing these synapses to be inhibitory. In addition, it was found that one of the axon terminals of the stellate cell synapsed with one of that cell's own dendrites. The significance of this finding is discussed.
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Effect of oestrogen on the pituitary gland of male Syrian hamsters. I. Electron microscope studies of pars intermedia.
The ultrastructure of the pars intermedia of normal and oestrogen-treated male Syrian hamsters is described. 3 types of cell were observed in normal gland, namely, 2 types of "light" cell and a "dark" cell. Light cells were regular in shape with round or oval nuclei and could be divided into type 1 and 2 by the size of their granules 200 to 250 nm in type 1 and 100 to 150 nm in type 2. Dark cells were fewer in number, irregular in outline with highly-indented chromatin-rich nuclei and occasional secretory granules in the Golgi area. Treatment for 6 weeks with diethylstibestrol (DES) 0.6 mg in 0.2 ml distilled water subcutaneously 3 times per week failed to induce recognisable change in the pars intermedia although after 12 weeks treatment cytoplasmic changes were observed. From that time until the experiment ended after 30 weeks of treatment progressive changes indicative of enhanced synthesis of hormone were present, greater cytoplasmic volume, hypertrophy of the Golgi apparatus, marked development of endoplasmic reticulum and ribosomes, increased numbers of secretory granules and the presence of granules within granules.
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Time- and dose-dependent influence of ouabain on the ultrastructure of optic neurones.
The cardiac glycoside ouabain was injected into the eye-bulb of the teleost fish, Carassius carassius. Three doses of ouabain were used: 10(-4) M, 10(-5) M, 10(-6) M. The final concentrations in the vitreous body of the eye were approximately 3-10(-5) M, 3-10-6 M and 3-10-7 M, respectively. After 8 hrs, 1, 2, 4, 6 and 8 days the ultrastructural alterations of retinal ganglion cells, the optic axons near the bulb and the terminal segments in the optic tectum were studied. The high doses of ouabain induced an early necrobiosis of the cell bodies in the retina followed by degeneration in the nerve. This is characterized as a protracted form of Wallerian degeneration. The significance of the inhibition of Na+ -K+-activated ATPase at the perikaryal level for both the integrity of axonal morphology and the axonal flow is discussed.
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NEDD4L induces mitochondrial dysfunction and neurodegeneration by promoting LIPT2 degradation in Huntington's disease.
Impairment of mitochondrial protein stability is associated with neurodegeneration in Huntington's disease (HD). However, the E3 ligase responsible for maintaining mitochondrial protein homeostasis in HD remains poorly understood. In this study, we demonstrate that NEDD4L protein levels are elevated in human striatal organoids (hSOs) derived from induced pluripotent stem cells of patients as well as in a mouse model of HD. Overexpression of NEDD4L leads to degeneration and cell death of medium spiny neurons (MSNs), along with a reduction in motor activities. Conversely, deletion of NEDD4L restores abnormal MSN morphology, corrects deficits in calcium signaling, alleviates neurodegeneration in HD-hSOs, and improves motor dysfunction observed in YAC128 mice. Mechanistically, NEDD4L disrupts mitochondrial function by binding to lipoyl(octanoyl) transferase 2 (LIPT2) and promoting its degradation through ubiquitination and lysosomal pathways. This process impairs lipoic acid biosynthesis and the lipoylation of E2 subunits of alpha-ketoglutarate dehydrogenase (α-KGDH E2). Furthermore, either overexpressing LIPT2 or administering lipoic acid mitigates neurodegeneration and rectifies deficits in motor coordination activity. These findings unveil a molecular mechanism underlying the regulation of lipoic acid metabolism and underscore the potential therapeutic role of protein lipoylation in the treatment of HD.
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Fine structure of the anterior neurohypophysis of the pond-loach, Misgurnus fossilis L., with reference to the neurosecretory innervation of intrinsic cells of the pars distalis.
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Axonal transport of proteins in the optic nerve and tract of the rabbit.
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Patterns of degeneration in the caudal cochlear nucleus of the cat after cochlear ablation.