Quote:Gay Lyon's ME/CFS Awareness fun fact of the day:

While science still doesn’t know the cause of ME/CFS, research has revealed the mechanics of how some of the symptoms occur. One key symptom is called Post Exertional Malaise (PEM) or Post Exertional Neuroimmune Exacerbation (PENE). In plain English that means that too much exertion, whether physical or mental, leaves you feeling sick and in pain, as if you have the flu, and it can take days to recover. If you try to push through it, you get worse.

Studies have shown that when people with ME/CFS exercise, they take in as much oxygen as healthy people, but the oxygen doesn’t get to the cells that need it. When a person exercises, the cells use oxygen to produce energy. That’s called aerobic exercise. If they exercise really hard or for a long time, they don’t get enough oxygen to keep up with the energy demand, and the body converts to other ways of producing energy; that’s called anaerobic exercise. That’s what leaves athletes bent over and huffing at the end of a 400 meter race. People with ME/CFS reach that crossover to anaerobic very quickly, in just a couple of minutes.

When a person with ME/CFS crosses over into anaerobic exercise, little on-off switches in the genes that control the autonomic nervous system go haywire. The autonomic nervous system (ANS) controls breathing, blood pressure, heart rate, stress response, digestion, temperature regulation, hormones, and a bunch of other things, and it’s an important immune system regulator. So when the ANS goes haywire, it sets off the immune system, and you end up feeling like you’ve got the flu. At the same time, the immune system doesn’t work to fight off pathogens the way it should. Plus all of the systems controlled by the ANS don’t work properly.

Scientists are starting to do research now to find out which genes have this out-of-whack reaction. Other researchers are trying to figure out what causes it. Some think ME/CFS may be an autoimmune disease, where the immune system mistakenly targets the body’s own tissues for destruction. Others think it may be caused by an unknown pathogen or combination of pathogens. A lot more research is needed.

Quote:Encephalitis is an uncommon but serious condition that causes inflammation of the brain.
Encephalitis usually begins with flu-like symptoms, such as a high temperature, a headache and joint pain.
More serious symptoms may then develop over the next few hours or days, including:
changes in mental state, such as confusion, drowsiness or disorientation
seizures (fits)
changes in personality and behaviour
Flu-like symptoms that rapidly get worse and affect mental state should be treated as a medical emergency. In these circumstances, dial 999 immediately and request an ambulance.
Read more about the symptoms of encephalitis.
Why does encephalitis happen?

There are several different types of encephalitis that have different causes. The most common are:
infectious – inflammation occurs as a direct result of an infection, which is often viral
post-infectious – inflammation is caused by the immune system reacting to a previous infection, and can occur days, weeks or sometimes months after the initial infection
autoimmune – inflammation is caused by the immune system reacting to a non-infectious cause, such as a tumour
chronic – inflammation develops slowly over many months, and can be the result of a condition such as HIV, though in some cases there is no obvious cause
There are also several types of encephalitis spread by mosquitoes – such as Japanese encephalitis – and ticks, such as tick-borne encephalitis. Encephalitis can also be caused by rabies.
Read more about the causes of encephalitis.
How is encephalitis treated?

Encephalitis needs urgent treatment, usually in a hospital intensive care unit (ICU). The earlier it's diagnosed, the more successful treatment is.
Treatment depends on the type of encephalitis you have, but may include:
anti-viral medication
steroid injections
immunosuppressants (medicines that stop the immune system from attacking healthy tissue)
Read more about diagnosing encephalitis and treating encephalitis.
Complications

Some people make a full recovery from encephalitis. But for many, encephalitis can lead to permanent brain damage and complications, including:
memory loss
epilepsy, a condition that causes repeated seizures
personality and behavioural changes
problems with attention, concentration, planning and problem solving
fatigue (extreme tiredness)

Quote:3. Targeting lipid metabolism, a novel antiviral strategy

Specific lipids are essential for multiple steps of the viral replication cycle and, therefore, different strategies can be used to interfere with virus infection. As a first approach to inhibit enveloped virus multiplication, the functions of lipids incorporated into the viral particle can be targeted by chemical compounds or even by antibodies [161]. This is the case of broad-spectrum antivirals, − some of them already licensed for human use, such as arbidol [162-164] −, or inhibitors of membrane fusion [3]. Impairment of viral fusion can be achieved also by targeting viral machinery involved in this process, a strategy currently assayed for HIV treatment [165].

An alternative, non-excluding lipid-targeted strategy to prevent viral multiplication is based on inhibitors of enzymes that catalyse lipid metabolic fluxes upregulated by viral infections [6]. Examples of compounds that act at distinct points of lipid metabolism and with reported antiviral activity in vitro are given in Table 4. Targeting lipid metabolism as an antiviral strategy raises important concerns. On one hand, alteration of such important metabolic pathway for cellular homeostasis may resemble a non-specific strategy, which could result in deleterious effects for the host. However, it should be also considered that currently antiviral compounds also target other major metabolic pathways, i.e. that of nucleic acids metabolism [166-169]. On the other hand, targeting host factors to avoid viral replication could also carry advantages. Drugs that target host factors seem to be less susceptible to the development of viral resistance than strategies focused on viral proteins. Another advantage of this approach is that compounds targeting a specific group of lipids can successfully inhibit replication of different unrelated viruses (Table 4), thus constituting candidates for broad-spectrum antiviral drugs. These facts make that the use of drugs that impair different aspects of lipid metabolism has been proposed as a feasible antiviral approach [1,6,14].

Target lipid
Inhibitor
Antiviral activity against
Refs.
Cholesterol
Statins
HIV, HCV, influenza
[170-176]
U18666A
DENV, HCV
[113,177]
Fatty acids
TOFA
HCMV, Influenza
[6]
C75
HCMV, DENV, YFV, WNV, Influenza, HCV, CVB3
[6,9,81,102,117,119]
Cerulenin
DENV, WNV, PV, CVB3
[81,102,117,121]
Arachidonate
HCV
[178]
Oleic acid
PV
[118]
PI4P
Enviroxime-like
PV, AiV
[108,109]
PIK93
PV, CVB3, CVB5
[81,93,109]
AL-9
HCV
[179]
Sphingolipids
Myriocin
Hepatitis B virus, HCV
[180-182]
Multiple
Valproic acid
VACV, WNV, SFV, SINV, ASFV, VSV, LCMV, USUV
[145]
Abbreviations used in this table: AiV, Aichi virus; ASFV, African swine fever virus; CVB, coxsackievirus B; C75, trans-4-carboxy-5-octyl-3-methylene-butyrolactone; DENV, Dengue virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; LCMV, lymphocytic chioriomeningitis virus; PV, poliovirus; SINV, Sindbis virus; SFV, Semliki Forest virus; TOFA, 5-tetradecyloxy-2-furoic acid; USUV, Usutu virus; VACV, vaccinia virus; VSV, vesicular stomatitis virus; WNV, West Nile virus; YFV, yellow fever virus

TABLE 4.
Examples of drugs targeting lipid metabolism with reported antiviral activity

Quote:Neuroscientist Patrik Verstreken of VIB (Flanders Institute for Biotechnology) and KU Leuven has shown for the first time that dysfunctional mitochondria in brain cells can lead to learning disabilities. The link between dysfunctional mitochondria and Parkinson's disease is known, but this new research shows that it is also present in other brain disorders.

Patrik Verstreken (VIB / KU Leuven): "This discovery shows that energy production in brain cells is the basis of various brain disorders. We hope that a better understanding of the mechanisms used by the cell to maintain optimum energy levels will lead in the long term to medical applications that prevent or cure these diseases."

Dysfunctional mitochondria toxic for the brain cell
Well-functioning mitochondria – the organelles that generate energy in cells – are essential for a healthy brain. They provide the energy needed for communication between brain cells, which is crucial for transmitting stimuli and signals and thus for optimal functioning of the body. Earlier research has shown that Parkinson's disease is often paired with dysfunctional mitochondria. Moreover, dysfunctional mitochondria are not efficiently discarded from the cell, which complicates the operation of other healthy mitochondria and leads to insufficient energy production in the cell. They can be compared to a faulty engine that emits toxic fumes.

Quality control by the brain cell

The Leuven-based VIB researchers Dominik Haddad, Vanessa Morais and Patrik Verstreken have unraveled the mechanism by which brain cells trigger the destruction of dysfunctional mitochondria. Once the mechanism is triggered, communication between brain cells is reestablished. The researchers were surprised to find that this mechanism is not only defective in Parkinson's disease, but also in specific cases of intellectual disability. These results indicate the wider importance of mitochondria for optimal functioning of our brains. Haddad, Morais and Verstreken hope that their insights eventually contribute to the prevention of various brain disorders.

Quote:While common in viral infections and neoplasia, spontaneous cell-cell fusion, or syncytialization, is quite restricted in healthy tissues. Such fusion is essential to human placental development, where interactions between trophoblast-specific human endogenous retroviral (HERV) envelope proteins, called syncytins, and their widely-distributed cell surface receptors are centrally involved. We have identified the first host cell-encoded protein that inhibits cell fusion in mammals. Like the syncytins, this protein, called suppressyn, is HERV-derived, placenta-specific and well-conserved over simian evolution. In vitro, suppressyn binds to the syn1 receptor and inhibits syn1-, but not syn2-mediated trophoblast syncytialization. Suppressyn knock-down promotes cell-cell fusion in trophoblast cells and cell-associated and secreted suppressyn binds to the syn1 receptor, ASCT2. Identification of the first host cell-encoded inhibitor of mammalian cell fusion may encourage improved understanding of cell fusion mechanisms, of placental morphogenesis and of diseases resulting from abnormal cell fusion.

Quote:Discussion

We are aware of no previous reports of a protein encoded by a mammalian genome that specifically inhibits cell fusion. The implications of this finding to human health and disease may be far-reaching. In the placenta, cytotrophoblast progenitor cells syncytialize into a continuous, multinucleated layer of terminally-differentiated fused cells that line the intervillous space; this layer is called the syncytiotrophoblast. The syncytiotrophoblast sheds cell-derived microparticles into the maternal circulation, likely via activation or apoptosis30, but certainly through processes that appear to be tightly regulated31, 32. While the exact control mechanisms for syncytiotrophobalst turnover remain undefined, it is clear that syn1 is involved in formation of syncytiotrophoblast and that several diseases of pregnancy, including intrauterine growth retardation (IUGR) and preeclampsia, are characterized by abnormal placental development and/or villous turnover32, 33. The possibility of central involvement of a placental inhibitor of syn1-induced syncytialization (i.e., suppressyn) in these disorders is enticing and indicates an important pathway for future investigations. While we have here described the cell fusion effects of suppressyn in syncytiotrophoblast models, syn1 and suppressyn are also detected in invasive EVT. Like abnormal syncytialization, shallow placental invasion is also characteristic of preeclampsia and IUGR, but also of spontaneous pregnancy loss33, 34. While the role of syn1 in placental invasion remains incompletely defined, the co-expression of syn1 and suppressyn at this maternal-fetal also promotes intriguing hypotheses. For example, the presence of suppressyn in EVT could be involved in the inhibition of EVT end-differentiation into non-invasive, HLA-G positive, non-secretory trophoblast giant cells20, 23, 25, 35.

In a remarkable example of convergent evolution, several mammalian species, including rodents, lagomorphs, Carnivora, and humans have co-opted endogenous retroviral envelope proteins for use in normal placental development36, 37, 38, 39. Also remarkable is the finding that, despite widely varying sequences and independent acquisition, human syn1 and rabbit syn-Ory1 can use the same neutral amino acid transporter, ASCT-2, as a receptor mediating cell fusion6, 38; the receptors for the murine synA and Carnivoral syncytin (syncytin-Car1) have not been identified. Our demonstration of direct binding of suppressyn to ASCT-2 supports an important role for suppressyn in human fusion events and predicts that a search for similar retrovirally-derived fusion-control proteins in other species is likely to be fruitful.

While a recent exciting description of syn1 expression and function in osteoclast fusion2 adds to the very limited evidence for tissue expression of syn1 among healthy organs other than the placenta, in diseased tissues, syn1 has been implicated in neoplastic cell fusion40 and ASCT2 appears to play roles in cancer aggression41 and in viral fusion. ASCT2 has been identified as the receptor for a diverse family of retroviruses, including baboon endogenous retrovirus, avian reticuloendothelial virus, feline endogenous virus (RD114), and type D simian retroviruses29. Syn1 can pseudotype HIV-1 viral cores42, likely through interactions with RD114 (ASCT2). We hypothesize that suppressyn-mediated inhibition of signaling through ASCT2 could help to explain the fairly robust ability of the human placenta to delimit vertical viral transmission, at least for a subset of exogenous pathogens.

Finally, it is intriguing to speculate on the possible function of Fb1 in its ancestral exogenous retrovirus. Several retroviruses have well-described mechanisms by which they downregulate the host cell surface receptors mediating their entry after infection has occurred43, 44. Like those that share ASCT2, many other retroviruses share alternate but common host surface receptors that mediate entry by any of the viruses in that particular family. The subset of viruses sharing a given receptor make up an interference group; those that utilize ASCT2 for entry into human cells comprise one of the largest of these groups: the RD114/type D interference group44. In this context, surface receptor downregulation after infection may function to inhibit superinfection by a second virus from the same interference group. This mechanism has been called superinfection resistance or viral interference. The Fb1 protein may have originally been part of a HERV-Fb virus-encoded mechanism to inhibit superinfection by other interference group members, including HERV-W, that shared preference for ASCT2-mediated entry into host cells. A similar role has been described for a murine gene called Fv4 that is derived from a murine leukemia virus (MuLV) Env-like sequence and can function in cellular resistance to MuLV infection45. Like our description of the effects of suppressyn on the syn1 receptor, ASCT2, interference by Fv4 has been hypothesized occur at the level of the MuLV receptor.

Quote:In the mid-2000s, David Markovitz, a scientist at the University of Michigan, and his colleagues took a look at the blood of people infected with HIV. Human immunodeficiency viruses kill their hosts by exhausting the immune system, allowing all sorts of pathogens to sweep into their host’s body. So it wasn’t a huge surprise for Markovitz and his colleagues to find other viruses in the blood of the HIV patients. What was surprising was where those other viruses had come from: from within the patients’ own DNA.

Quote:The world of our inner viruses is still a murky, mysterious one that scientists are still surveying. And Markovitz’s discovery enabled him to add considerably to our understanding of these shadowy creatures. He discovered new members of a particularly interesting class of endogenous retroviruses–ones that, even today, can still have life breathed into them.

Markovitz and his colleagues analyzed the sequence of the virus genes they found in the patients with HIV. The genes belonged to a family of endogenous retroviruses called HERV-K, but they were not quite like any known HERV-K virus previously found.

The Michigan scientists wondered if this new HERV-K virus was hidden in the human genome. They checked the most complete draft of the human genome and couldn’t find a match. They knew that the human genome sequence was only about 95% finished, so they turned instead to the chimpanzee genome, on the off chance that the virus had infected the common ancestor of humans and chimpanzees over six million years ago. Bingo: a single copy of the virus turned up in the chimp genome. They dubbed it K111.

Having found this match, the scientists decided to return to the human genome and search for K111. They isolated DNA from their HIV patients, as well as from healthy people. They then split apart the two strands of the DNA and added a short piece of DNA that would bind to K111, should it be lurking there. In all 189 of their subjects, the scientists found the virus’s DNA.

Remarkably, though, the scientists didn’t find just one copy of K111 in each of their subject’s genomes, as is the case in chimps. The more the scientists looked, the more variants they found. Some K111 viruses were fairly intact, while others were vestiges. The scientists found over 100 copies of the virus in the human genome, scattered across fifteen chromosomes.

To figure out the origin of K111, the scientists looked back at other primates. They couldn’t find a version of K111 in any species other than chimpanzees. They concluded that the virus infected our ancestors not long before the split between humans and chimpanzees roughly six million years ago.

To find out what happened next, Markovitz and his colleagues turned to the genomes of extinct humans. Svante Paabo of the Max Planck Institute and his colleagues have sequenced the Neanderthal genome, as well as the genome of a lineage of mysterious cousins of Neanderthals, known as Denisovans. Our own ancestors diverged from those of Neanderthals and Denisovans about 800,000 years ago. Markovitz and his colleagues looked for K111 in their genomes, and there it was. The scientists found seven copies of K11 in Neanderthal DNA and four in the Denisovan genome.

This finding suggests that between 6 million and 800,000 years ago, K111 was duplicated a few times at a fairly slow pace. It’s possible that Markowitz and his colleagues missed some other copies because the reconstruction of those ancient genomes wasn’t quite accurate enough for their search. But even if we generously assumed that Neanderthals and Denisovans had twenty K111 viruses apiece, that’s still a small fraction of the 100 or more copies of K111 the scientists found in the human genome. It was only later, in the past 800,000 years, that K111 started proliferating at a faster pace.

One reason that K111 has gone overlooked till now is that it found a good place to hide–the center of chromosomes. This region, called the centromere, is a genomic Bermuda Triangle. It’s loaded with lots of short, repetitive stretches of DNA. When scientists reconstruct the sequence of a genome, they break DNA down into many overlapping segments, which they then try to rebuild based on overlapping similarities. Centromere DNA is so similar to itself that it’s easy to line up fragments in many different arrangements. As a result, centromeres make up much of the last 5% of the human genome that has yet to be mapped.

Another reason K111 has been able to hide for so long is that it’s fairly feeble. It lacks genes to make shells, so it can’t escape from its host cells any more. In fact, it was our own centromeres that appear to have made all the extra copies of K111. The repeating DNA in centromeres is not just tricky for human gene sequencers. It’s also tricky for the enzymes in a cell that make new copies of our DNA. They can slip up and accidentally swap segments from two chromosomes. K111 was thus able to spread from the centromere of one chromosome to another. Our cells also stutter sometimes when they try to copy centromere DNA, making extra copies of segments there. Markovitz and his colleagues argue that this is how new copies of K111 proliferated within each centromere.

Ironically, it was the HIV in the patients Markovitz and his colleagues studied which brought K111 back to light. When people get infected with HIV, the virus makes a protein called Tat which uncoils tightly wound stretches of human DNA, which allows its host cell to make more HIV at a faster rate.

Markovitz and his colleagues wondered if the Tat in their HIV-infected patients was spurring cells to also make copies of K111. To find out, they injected Tat proteins into human cells that were free of HIV. As they predicted, out came new genes for K111.

It’s conceivable that K111 interacts with HIV to contribute to AIDS, but Markovitz and his colleagues found no evidence of that. It’s certainly worth investigating further. But there’s another reason to keep learning about K111. Now that scientists have discovered K111, they can look for more copies of it in centromeres. Markovits suggests that their distinctive genes might serve as a kind of genetic barcode that could help genome mappers orient themselves in the hall of mirrors that is centromere DNA. Perhaps the human genome sequence will finally be completely mapped thanks to a virus that has been hiding in it for six million years.

(For more information, see my book, A Planet of Viruses.)

Quote:Abstract

Human Endogenous Retroviruses (HERVs) make up 8% of the human genome. The HERV-K (HML-2) family is the most recent group of these viruses to have inserted into the genome, and we have detected the activation of HERV-K (HML-2) proviruses in the blood of patients with HIV-1 infection. We report that HIV-1 infection activates expression of a novel HERV-K (HML-2) provirus, termed K111, present in multiple copies in the centromeres of chromosomes throughout the human genome, yet not annotated in the most recent human genome assembly. Infection with HIV-1 or stimulation with the HIV-1 Tat protein leads to the activation of K111 proviruses. K111 is present as a single copy in the genome of the chimpanzee, yet K111 is not found in the genomes of other primates. Remarkably, K111 proviruses appear in the genomes of the extinct Neanderthal and Denisovan, while modern humans have at least 100 K111 proviruses spread across the centromeres of fifteen chromosomes. Our studies suggest that the progenitor K111 integrated before the Homo-Pan divergence and expanded in copy number during the evolution of hominins, perhaps by recombination. The expansion of K111 provides sequence evidence suggesting that recombination between the centromeres of various chromosomes took place during the evolution of humans. K111 proviruses show significant sequence variations in each individual centromere, which may serve as markers in future efforts to annotate human centromere sequences. Further, this work is an example of the potential to discover previously unknown genomic sequences through the analysis of nucleic acids found in the blood of patients.

Quote:Despite these overall advances, the sequence of cellular and molecular events that leads to neuronal cell demise in TSEs remains obscure [168, 169]. At present, one envisions that neuronal cell death results from several parallel, interacting or sequential pathways involving protein processing and proteasome dysfunction [170], oxidative stress [159, 171], apoptosis and autophagy [172].

Quote:4.1.2. AUTOPHAGY IN PRION-INFECTED NEURONS

Prion propagation involves the endocytic pathway, specifically the endosomal and lysosomal compartments that are implicated in trafficking and recycling, as well as the final degradation of prions. Shifting the equilibrium between propagation and lysosomal clearance impairs the cellular prion load. This and the presence of autophagic vacuoles in prion diseased neurons [173, 174] suggest a role for autophagy in prion infection (reviewed in [172]). Indeed, the high numbers of autophagic vacuoles observed in neurons from experimentally prion-infected mice (Fig. 4A, B, Fig. 5) and hamsters is indicative of a robust activation of autophagy [175, 176]. Furthermore, autophagic vacuoles and multivesicular bodies have been detected in prion-infected neuronal cells in vitro [177].The formation of autophagic vacuoles has recently been observed in neuronal pericarya, neurites and synapses of neurons experimentally infected with scrapie, CJD and GSS [174], as well as in neuronal synaptic compartments in humans with certain PrD [173]. PrDs are further correlated with autophagy given that the Scrg1 protein (encoded by the scrapie responsive gene1, Scrg1) is upregulated in scrapie and BSE-infected brains, as well as in brains of patients with sporadic CJD [178-180] and is associated with neuronal autophagosomes [181, 182]. This Scrg1 protein is thus, a new marker for autophagic vacuoles in prion-infected neurons (Fig. 4A, B). In the brains of CJD and FFI patients and experimentally scrapie-infected hamsters, increased cytoplasmic levels of LC3-II-immunostained autophagosomes have been demonstrated in neurons, again indicating autophagy activation. In addition, the decreased p62 and polyubiquitinated proteins levels in hamster and human brains infected with prion suggest an upregulation of autophagy with enhanced autophagic flux and protein degradation. Downregulation of the mTOR pathway and upregulation of the beclin 1 pathway in these infected tissues provide further evidence of autophagy activation [183]. On the basis of these observations, Xu et al. [183] propose that neuronal autophagy is an intricate element of prion infections. They suggest that once PrPSC enters host cells and is delivered to endosomes, it accumulates in amphisomes via fusion with autophagosomes and then with lysosomes. At this initial stage of infection, PrPSC does not co-localize with autophagosomes, probably because PrPSC levels are too low to be detected due to their rapid degradation in autophagolysosomes. In agreement with this explanation, blocking the fusion of autophagosomes with lysosomes using bafilomycin A1 permits the visualization of PrP-PG14 and PrPSC in autophagosomes [183], as is the case for Aβ1-42 [184].

The role of lysosomes in PrDs is still controversial. Although autophagic lysosomal degradation of PrPSC in infected neurons is supposed to clear prion aggregates and inhibit PrPSC replication, there are indications that PrPSC may subvert the autophagic-lysosomal system to promote the conversion of PrPC into PrPSC. Lysosomal inhibitors prevent the build-up of PrPSC [126] and agonists of the autophagy-lysosome pathway enhance the clearance of PrPSC [185, 186, 126]. However, as PrPSC production increases, the accumulating PrPSC may saturate the clearance capacity of the system causing lysosomal disruption and release of PrPSC aggregates into the neuroplasm. In turn this would cause cell stress and over-activate autophagy, as has been reported in prion-diseased brain tissue [183].

The octapeptide repeats region of PrPC has been shown to negatively influence autophagy. As measured by LC3-II expression, autophagy induced by serum deprivation occurs earlier and to a greater extent in hippocampal neurons from ZH-I PrnP-/- compared with those from wild type mice. Reintroduction of PrPC, but not PrPC lacking its N-t octapeptide region, into ZH-I PrnP-/-neurons delays this upregulation of autophagy [187]. The transconformation of PrPC into PrPSC could interfere with the function of this domain and as a consequence, upregulate autophagy. It is conceivable that the activation of autophagy observed in PrD models reflects a defense mechanism designed to degrade prions and resist oxidative stress. A reduction in autophagy combined with endosomal/lysosomal dysfunction has indeed been proposed to contribute to the development of PrD [188]. Furthermore, the anti-cancer drug imatinib has been shown to activate lysosomal degradation of PrPSC [186] and is a potent autophagy inducer [189]. When administered early during peripheral infection, imatinib delays both PrPSC neuroinvasion and the onset of clinical disease in prion-infected mice [190]. Upregulation of autophagy has beneficial effects on the clearance of aggregate-prone proteins in PrD and other neurodegenerative diseases [66, 111-115, 191, 192]. Both lithium and trehalose enhance PrPSC clearance from prion-infected cells by inducing autophagy, as demonstrated by increases in LC3-II protein and the number of GFP-LC3 puncta [193, 126]. Furthermore, PrPSC can be cleared not only by mTOR-independent autophagy (lithium and trehalose), but also by the mTOR-dependent route because the mTOR inhibitor rapamycin also causes a decrease in cellular PrPSC. Lithium-induced autophagy also reduces PrPC levels. This treatment causes internalization of PrPC [194], and the consequent reduction of available membrane-bound PrPC is known to decrease its conversion into pathologic PrPSC [195-198]. This would provide an additional, indirect way to reduce PrPSC by reducing of PrPC with lithium treatment.

Whether autophagy-inducing compounds are candidates for therapeutic approaches against prion infection has recently been investigated in prion-infected mice. Starting in the last third of the incubation periods, treatment with rapamycin and to a lesser extent with lithium significantly prolonged incubation times compared to mock-treated control mice [126, 172]. Along this line, activation of the class III histone deacetylase Sirtuin 1 (Sirt1) has been shown to mediate the neuroprotective effect of resveratrol against prion toxicity [199] and prevent prion protein-derived peptide 106-126 (PrP106-126) neurotoxicity via autophagy processing [200]. Moreover, Sirt1-induced autophagy protects against mitochondrial dysfunction induced by PrP106-126, whereas siRNA knockdown of Sirt1 sensitizes cells to PrP106-126-induced cell death and mitochondrial dysfunction. Finally, knockdown of Atg5 decreases LC3-II protein levels and blocks the effect of a Sirt1 activator against PrP106-126-induced mitochondrial dysfunction and neurotoxicity. Thus inducing Sirt1-mediated autophagy may be a principal neuroprotective mechanism against prion-induced mitochondrial apoptosis. Nevertheless, understanding the mechanisms underlying Sirt1-mediated autophagy against prion neurotoxicity and mitochondrial damage merits further investigation, in particular determining the Sirt1-mediated dowstream signaling network, including FOXOs, p53 and PGC-1α. More recently, the mTOR inhibitor and autophagy inducer rapamycin has been shown to delay disease onset and prevent PrP plaque deposition in a mouse model of the Gerstmann-Sträussler-Scheinker PrD [127]. Here, the reduction in symtom severity and prolonged survival correlate with increases in LC3-II levels in the brains of treated mice, suggesting that autophagy induction enhances elimination of misfolded PrP before plaques form. This is in agreement with the well known neuroprotective effects of rapamycin in various models of neurodegenerative diseases with misfolded aggregate-prone proteins (e.g. PD [111], ALS [201], HD [115], spinocerebellar ataxia [66, 202], FTD [203] and AD [41, 124, 125].