Edellistä sukupolvea (1920 aikaan)
https://www.genecards.org/cgi-bin/carddisp.pl?gene=SMPD3&keywords=SMPD3
GALC säätelyhäiriössä ilmeinen locus minor resistentiae : munuainen.
Munuaistuumorissa osallisuutta
GALC säätelyllä ja SMPD3 säätymisellä https://pmc.ncbi.nlm.nih.gov/articles/PMC8946824/figure/F1/
https://www.genecards.org/cgi-bin/carddisp.pl?gene=PSAP&keywords=Psychosine
https://www.genecards.org/cgi-bin/carddisp.pl?gene=PSAP&keywords=PSAP
Psychosiini eli galaktoosisfingosiini on välituote, jonka pitoisuus on hyvin matala normaalisti ja siitä tulee vapaata D-galaktoosia ja sfingosiinia. ,jotka ovat oligodendrosyyteille neurotoksisia.
Saponiinien joukko siivoaa näitä ja nopeuttaa myeliiniin asettuvien glykolipidien degradaatiota.. aivojen lipidien turnover prosessissa. SAPLIP family:
PSAP 10q21.1
Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate. ( SAP_HUMAN,P07602 )
Saposin-B stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases. ( SAP_HUMAN,P07602 )
Saposin-D is a specific sphingomyelin phosphodiesterase activator (EC 3.1.4.12). ( SAP_HUMAN,P07602 )
[Prosaposin]: Behaves as a myelinotrophic and neurotrophic factor, these effects are mediated by its G-protein-coupled receptors, GPR37 and GPR37L1, undergoing ligand-mediated internalization followed by ERK phosphorylation signaling. ( SAP_HUMAN,P07602 )
Saposins are specific low-molecular mass non-enzymic proteins, they participate in the lysosomal degradation of sphingolipids, which takes place by the sequential action of specific hydrolases. ( SAP_HUMAN,P07602 )
https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2014.00137/full
Vuoden 2014 käsitys aivojen sinkin tärkeydestä ja funktioista.. Kaavassa oli vielä kysymysmerkin kohtia.REVIEW article
Front. Aging Neurosci., 25 June 2014
Sec. Cellular and Molecular Mechanisms of Brain-aging
Volume 6 - 2014 | https://doi.org/10.3389/fnagi.2014.00137
This article is part of the Research TopicThe Molecular Pathology of Cognitive Decline: Focus on MetalsView all 19 articles
Normal ageing is characterized by cognitive decline across a range of neurological functions, which are further impaired in Alzheimer’s disease (AD). Recently, alterations in zinc (Zn) concentrations, particularly at the synapse, have emerged as a potential mechanism underlying the cognitive changes that occur in both ageing and AD. Zn is now accepted as a potent neuromodulator, affecting a variety of signaling pathways at the synapse that are critical to normal cognition. While the focus has principally been on the neuron: Zn interaction, there is a growing literature suggesting that glia may also play a modulatory role in maintaining both Zn ion homeostasis and the normal function of the synapse. Indeed, zinc transporters (ZnT’s) have been demonstrated in glial cells where Zn has also been shown to have a role in signaling. Furthermore, there is increasing evidence that the pathogenesis of AD critically involves glial cells (such as astrocytes), which have been reported to contribute to amyloid-beta (Aβ) neurotoxicity. This review discusses the current evidence supporting a complex interplay of glia, Zn dyshomeostasis and synaptic function in ageing and AD.
Ageing is an inevitable biological process wherein physical and mental capabilities are diminished over time, often resulting from a variety of factors such as cumulative oxidative stress and altered cell metabolism. This functional decline then ultimately results in a loss of synaptic plasticity. Ageing in itself does not require a treatment per se, but maintaining cognitive function into old age is a concept many aspire to. Currently, normal ageing is considered to be associated with an overall decline in cognition occurring via structural and functional brain changes over a period of time (Meunier et al., 2014). While we have a strong understanding of the physical decline that occurs in peripheral organs and systems (e.g., muscle and bone); the particular molecular and cellular changes that occur within the brain and which ultimately underlie the progression of normal ageing are yet to be fully determined. Despite the lack of consensus on the precise neural alterations that occur, it is clear that there is a fine line between healthy and pathological ageing.
Currently, the mechanisms underlying ageing within the brain remain poorly understood, and indeed one of the hallmarks of ageing is its variability (Meunier et al., 2014), with the preservation or loss of cognitive functions differing between individuals. The functional memory decline that does occur, however, is actually well characterized, with executive functioning, processing speed and reasoning ability declining from middle age (Deary et al., 2009). While the molecular and cellular mechanisms underlying this are yet to be fully elucidated, it is important to note the potential intersection with pathological ageing, as seen in conditions such as Alzheimer’s disease (AD). Ageing is the greatest risk factor for the development of AD, which is the most common form of age-related dementia (Mosconi et al., 2010; Reitz et al., 2011), and it has been suggested that AD may simply be an acceleration of the normal ageing process. Indeed, many of the cognitive impairments seen in normal ageing are further exacerbated in AD. Symptomatically, AD is characterized by marked deficiencies in episodic memory, attention, perception and speech (Mesulam, 1999) as well as altered mood (Lopez et al., 2001). Pathologically it is defined by the accumulation of intracellular neurofibrillary tangles (comprised of abnormally phosphorylated tau protein) and extracellular plaques (comprised of misfolded forms of the amyloid-β (Aβ) peptide) within the brain. With regards to the potential for a mechanistic overlap between ageing and AD, recent evidence points to zinc (Zn) homeostasis as key player in both normal and pathological ageing. Specifically, it has been demonstrated that there is a modulation in brain Zn homeostasis in both ageing and AD (Religa et al., 2006; Haase and Rink, 2009) that results in a neuronal Zn deficiency that may ultimately underlie the onset and progression of cognitive deficits seen in both.
Zn; an essential trace element and second in abundance in mammalian tissues (Wang et al., 2005; Paoletti et al., 2009), is critical for immunity, growth and development (Nolte et al., 2004), is a cofactor for more than 300 enzymes and is essential for the correct functioning of over 2000 transcription factors (Takeda, 2000; Levenson and Tassabehji, 2007; Jeong and Eide, 2013). The brain has the largest Zn content (Vasto et al., 2008), the levels of which are tightly controlled by three main families of proteins that have a distinct tissue and cell level pattern of localization and expression (Hennigar and Kelleher, 2012). These are; the metallothioneins (MT’s; that also coordinate a variety of other metal ions), zinc transporters (ZnT’s) and Zn-regulated and iron-regulated transporter proteins (ZIP’s; recent evidence has also implicated the presenilin family as capable of influencing Zn concentrations (Greenough et al., 2013)). Currently there are four MT isoforms, 10 ZnT’s, 15 ZIP’s and two presenilins. The ZnT’s coordinate intracellular Zn homeostasis while the ZIP’s primary function is to regulate Zn uptake (Guerinot, 2000). The role of the MT’s is to control cytosolic concentrations through the binding and distribution of Zn (Mocchegiani et al., 2001). A number of studies have examined the effect of altered MT on brain metal levels, with mice deficient in both MT-I/II (Manso et al., 2011) and MT-III (Erickson et al., 1997), for example, shown to have altered brain Zn levels. Cumulatively, these proteins are responsible for the influx and efflux of Zn2+ in a variety of cellular compartments, including vesicles, Golgi apparatus, and mitochondria (Figure 1).
Microglia also release cytokines, which have central physiological roles in synaptic plasticity, neurogenesis and learning and memory in the normal brain (Morris et al., 2013) possibly through their influence on MT expression and hence Zn concentration (Vasto et al., 2008). Microglia may, however, have a more direct role in Zn homeostasis as Higashi et al. (2011) recently learned. Microglia can directly uptake Zn via ZIP1, which is also a trigger for sequential microglial activation. In a study by Knoch et al. (2008) the release of intraneuronal Zn2+ and a subsequent increase in neuronal voltage-gated K+ currents as caused by the release of ROS from activated microglia lead to neuronal cell death. This suggests the primary mechanism of neuronal apoptosis may in fact, be the earlier damage to glial cells. This is accordance with findings by Kaindl et al. (2008, 2012) that activation of microglial NMDA receptors results in an increase in oxidative stress in vitro (Kaindl et al., 2008, 2012). Glial senescence during ageing can also impact normal synapse function (Wong, 2013) and result in aberrant connectivity between neurons.
Both Zn and glia appear to have multifarious roles within the brain, especially within synapses. Indeed, synaptic loss is the fundamental feature of the ageing brain that links neuropathology to cognitive decline in AD (Talantova et al., 2013). This is largely applicable to pathological ageing and neurodegenerative disorders such as AD wherein the abnormal deposition of misfolded Aβ peptide into plaques, which bind Zn, results in a significant decrease in intracellular Zn (Bush et al., 1994). Moreover, the plaques are in abundance in brain areas with high densities of glutamatergic synapses such as the hippocampus, exhibiting a similar distribution to that of Zn with glutamatergic neurons. Additionally, microglia have been suggested to play a role in plaque formation (Stollg and Jander, 1999). Further research by Desphande et al. (2009) clearly demonstrated oligomers of Aβ interfering with synaptic function, suggesting that Zn at the NMDA receptor attracts the Aβ in addition to its high binding affinity to synapses. Keeping the aforementioned information in mind, it is reasonable to suggest that AD may be the result of synaptic dysfunction caused by a disruption of the fine and complex interplay between Zn, neuronal, glial and microglial communication that occurs within the synapse. Due to the high binding affinity of Aβ to both Zn and synapses, upon activation of the pre-synaptic neuron and the subsequent release of Zn into the synapse, the Zn can be captured by the Aβ and lodged within the plaque to ultimately disrupt synaptic transmission. A decrease in available Zn for neurotransmission and calcium signaling then causes downstream errors that may result in further Zn dyshomeostasis in a negative feedback loop eventually leading to glial damage and apoptosis through microglial activation. Disruption of cytokine signaling and failure of the signaling mechanisms maintaining the phenotype of microglia in the normal brain may contribute to learning and memory dysfunction and synaptic pathologies such as AD or dementia which, in some of its forms, is at its onset a result of a failure to maintain microglia in their ramified state (Morris et al., 2013). A diagrammatic representation of the change in Zn2+ in the progression from normal to pathological ageing is illustrated in Figure 3.
Herein evidence supporting a link between Zn, glia and cognitive decline has been presented and discussed. The research thus far suggests the possibility of a feedback loop between Zn homeostasis, synaptic excitation, neurons, astrocytes and microglia. Perhaps the most appropriate definition is that of Morris et al. (2013) that a synapse is “a complex, dynamic and often transient structure involving several cells interacting with a sophisticated extracellular matrix and milieu”. The contribution of microglia and astrocytes to synaptic plasticity mechanisms relevant to learning and memory must be included in studies. Only by including these cell types in future research will we come to truly understand the intricate molecular mechanisms underlying the ageing processes; thereby discovering potential avenues for intervention to ensure that we are able to enjoy our twilight years to the best of our cognitive ability.
https://www.genecards.org/cgi-bin/carddisp.pl?gene=PREP&keywords=prolyl,endopeptidase
Article| Volume 94, ISSUE 2, P161-170, July 24, 1998
Mainitaan amnesiasairauksiin assosiaatiota 1998.
https://www.frontiersin.org/articles/10.3389/fnmol.2017.00456/full
https://www.genecards.org/cgi-bin/carddisp.pl?gene=EGR1&keywords=EGR
The protein encoded by this gene belongs to the EGR family of C2H2-type zinc-finger proteins. It is a nuclear protein and functions as a transcriptional regulator. The products of target genes it activates are required for differentitation and mitogenesis. Studies suggest this is a cancer suppressor gene. [provided by RefSeq, Dec 2014]
EGR1 (Early Growth Response 1) is a Protein Coding gene. Diseases associated with EGR1 include Ischemia and Monocytic Leukemia. Among its related pathways are PIP3 activates AKT signaling and Hepatocyte growth factor receptor signaling. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and transcription factor binding. An important paralog of this gene is EGR3.
Transcriptional regulator (PubMed:20121949). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3'(EGR-site) in the promoter region of target genes (By similarity). Binds double-stranded target DNA, irrespective of the cytosine methylation status (PubMed:25258363, 25999311). Regulates the transcription of numerous target genes, and thereby plays an important role in regulating the response to growth factors, DNA damage, and ischemia. Plays a role in the regulation of cell survival, proliferation and cell death. Activates expression of p53/TP53 and TGFB1, and thereby helps prevent tumor formation. Required for normal progress through mitosis and normal proliferation of hepatocytes after partial hepatectomy. Mediates responses to ischemia and hypoxia; regulates the expression of proteins such as IL1B and CXCL2 that are involved in inflammatory processes and development of tissue damage after ischemia. Regulates biosynthesis of luteinizing hormone (LHB) in the pituitary (By similarity). Regulates the amplitude of the expression rhythms of clock genes: BMAL1, PER2 and NR1D1 in the liver via the activation of PER1 (clock repressor) transcription. Regulates the rhythmic expression of core-clock gene BMAL1 in the suprachiasmatic nucleus (SCN) (By similarity). ( EGR1_HUMAN,P18146 )
Sara M. Hancock
David I. Finkelstein2
Paul A. Adlard