RNA and neurodegenerative diseases

This 2018 Chinese paper reviewed the associations among long non-coding RNA and four neurodegenerative diseases:

“lncRNAs are widely implicated in various physiological and pathological processes, such as epigenetic regulation, cell cycle regulation, cell differentiation regulation, cancer, and neurodegenerative diseases, through their interactions with chromatin, protein, and other RNAs. Numerous studies have suggested that lncRNAs are closely linked with the occurrence and development of a variety of diseases, especially neurodegenerative diseases, of which the etiologies are complicated and the underlying mechanisms remain elusive.

We focus on how lncRNA dysfunctions are involved in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.”

Table 1 showed specific lncRNAs that acted as “bodyguards” in inherited Huntington’s disease, “culprits” in Alzheimer’s disease, and as both in Parkinson’s disease. The table didn’t include lncRNAs associated with amyotrophic lateral sclerosis although the review text mentioned several.

https://www.sciencedirect.com/science/article/pii/S2162253117303104 “Long Non-coding RNAs, Novel Culprits, or Bodyguards in Neurodegenerative Diseases”


Differing approaches to a life wasted on beliefs

Let’s start by observing that people structure their lives around beliefs. As time goes on, what actions would a person have taken to ward off non-confirming evidence?

One response may be that they would engage in ever-increasing efforts to develop new beliefs that justified how they spent their precious life’s time so far.

Such was my take on the embedded beliefs in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684598/pdf/PSYCHIATRY2017-5491812.pdf “Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions”:

“Animal models have shown the benefits of continued environmental enrichment (EE) on psychopathological phenotypes, which carries exciting translational value.

This paper posits that psychotherapy serves as a positive environmental input (something akin to EE).”

The author conveyed his belief that wonderful interventions were going to happen in the future, although, when scrutinized, most human studies have demonstrated null effects of psychotherapeutic interventions on causes. Without sound evidence that treatments affect causes, this belief seemed driven by something else.

The author saw the findings of research like A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms as supporting external interventions to tamp down symptoms of patients’ presenting problems. Did any of the paper’s 300+ citations concern treatments where patients instead therapeutically addressed their problems’ root causes?

For an analogous religious example, a person’s belief caused him to spend years of his life trying to convince men to act so that they could get their own planet after death, and trying to convince women to latch onto men who had this belief. A new and apparently newsworthy belief developed from his underlying causes:

“The founder and CEO of neuroscience company Kernel wants “to expand the bounds of human intelligence”. He is planning to do this with neuroprosthetics; brain augmentations that can improve mental function and treat disorders. Put simply, Kernel hopes to place a chip in your brain.

He was raised as a Mormon in Utah and it was while carrying out two years of missionary work in Ecuador that he was struck by what he describes as an “overwhelming desire to improve the lives of others.”

He suffered from chronic depression from the ages of 24 to 34, and has seen his father and stepfather face huge mental health struggles.”

https://www.theguardian.com/small-business-network/2017/dec/14/humans-20-meet-the-entrepreneur-who-wants-to-put-a-chip-in-your-brain “Humans 2.0: meet the entrepreneur who wants to put a chip in your brain”

The article stated that the subject had given up Mormonism. There was nothing to suggest, though, that he had therapeutically addressed any underlying causes for his misdirected thoughts, feelings, and behavior. So he developed other beliefs instead.

What can people do to keep their lives from being wasted on beliefs? As mentioned in What was not, is not, and will never be:

“The problem is that spending our time and efforts on these ideas, beliefs, and behaviors won’t ameliorate their motivating causes. Our efforts only push us further away from our truths, with real consequences: a wasted life.

The goal of the therapeutic approach advocated by Dr. Arthur Janov’s Primal Therapy is to remove the force of the presenting problems’ motivating causes. Success in reaching this goal is realized when patients become better able to live their own lives.

Epigenetic effects on genetic diseases

This 2017 review provided evidence for epigenetic effects on a disease widely considered to be of genetic origins:

“..for a T1D [type 1 diabetes] identical twin the concordance rate (both twins affected)..is consistently less than 100%, which implies a non-genetically determined effect. However, the concordance rate declines with age at diagnosis of the index twin, indicating that in adult-onset T1D the genetic impact is limited, and certainly lower than that in childhood-onset disease.

Genes associated with T1D are well-established and have four broad functions..However, T1D is unlikely to be a single disease since there is disease heterogeneity..the incidence of T1D has even increased several-fold in the last 30 years-a timeframe which rules out genetic evolution. In addition, studies of the incidence of T1D in migrant populations have shown a convergence towards the risk of the host population.

Alongside histone modifications and transcription factors, several cis-regulatory elements, including enhancers, promoters, silencers and insulators, are crucial to the function of the genome..There are more than a million enhancers; therefore, many more than there are genes, so that a number of genes are regulated by the same enhancer, which may co-localise with CpGs. Gene enhancers can be found upstream or downstream of genes and do not necessarily act on the closest promoter..Enhancers may be accompanied by insulators, which are located between the enhancers and promoters of adjacent genes and can limit phenotypic gene expression despite genetic activation.”

The review was weak in a few areas. The authors repeated a laughable claim for gross national product as a non-genetic effect for Type 1 diabetes. They also made other hyperbolic statements such as “..this observation illustrates the power of epigenetic analysis to identify those cells which are actively using the genes associated with a given tissue, given that all cells contain every gene..” that were out of place with the review’s evidential bases.

https://link.springer.com/article/10.1007/s11892-017-0916-x “The Role of Epigenetics in Type 1 Diabetes”

Improved methodology in studying epigenetic DNA methylation

This 2015 New York human study was of:

“The two major populations of human prefrontal cortex neurons..the excitatory glutamatergic projection neurons and the inhibitory GABAergic interneurons which constitute about 80% and 20% of all cortical neurons, respectively.

Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG).

A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons.

Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype-specific gene expression compared to CpG methylation.”

The researchers performed numerous cross checks to test the results of their methodologies. This was necessary because, for example, studies such as A human study of changes in gene expression point out that current technologies such as the 450K array:

“Queries only 1.6% of all CpGs in the genome and the CpG selection is biased towards CpG islands.”

From the Discussion section:

“The higher abundance of hmCpG sites in GLU versus GABA neurons appears indicative of a difference in transcriptional potential between the neuronal subtypes. The increased hydroxymethylation could enable certain genes (e.g. activity-dependent genes) to be more readily induced in GLU versus GABA neurons.

These findings emphasize the importance of even subtle differences in the promoter CpG methylation for neuron subtype-specific gene expression. They also suggest that differences in CpG methylation within gene bodies and distal regulatory elements are not always directly reflected in differences in gene expression between neuronal subtypes.

The functional relevance of the association between gene expression and distal non-CpG methylation remains to be characterized.

Our data suggest that, compared to GABA interneurons, GLU projection neurons are characterized by more permissive chromatin state that is less constrained by repressive DNA methylation marks and is instead controlled by more dynamic means of transcription inhibition, such as non-coding RNAs and/or histone modifications.”

This study was similar to A problematic study of DNA methylation in frontal cortex development and schizophrenia in examining:

“If common risk variants determined by the recent genome wide associated studies (GWAS) for several neuropsychiatric diseases including schizophrenia (SCZ), autism spectrum disorder (ASD), major depressive disorder (MDD), and Alzheimer’s disease (AD) significantly overlap.

These findings strongly suggest an association between the epigenetic specification of both GABA and GLU neurons and SCZ. Risk variants associates with ASD, MD, or AD were not enriched.

An alternative explanation of our negative results could be the involvement of different developmental stages and/or brain regions in different diseases.”

The current study performed more detailed analyses, but on fewer subjects. The emphasis was on demonstrating an improved methodology.

Both studies’ findings regarding disease were of effects, not causes. That both study designs were limited to the postmortem prefrontal cortex reminded me of the old joke about looking for lost keys under the street light because the light was better there. At least the current study acknowledged the existence of other areas to search.

http://nar.oxfordjournals.org/content/early/2015/11/25/nar.gkv1304.full “Substantial DNA methylation differences between two major neuronal subtypes in human brain”

A review of genetic and epigenetic approaches to autism

This 2015 Chicago review noted:

“Recent developments in the research of ASD [autistic spectrum disorder] with a focus on epigenetic pathways as a complement to current genetic screening.

Not all children with a predisposing genotype develop ASD. This suggests that additional environmental factors likely interact with the genome in producing ASD.

Increased risk of ASD is associated with mutations in genes that overlap with chromatin remodeling proteins, transcriptional regulators and synapse-associated proteins. Interestingly, these genes are also targets of environmentally induced changes in gene expression.”

Evidence was discussed for both broad and specific epigenetic ASD causes originating in the prenatal environment:

  • Maternal stress:

    “Prenatal stress exerts a profound epigenetic influence on GABAergic interneurons by altering the levels of proteins such as DNMT1 and Tet1 and decreasing the expression of various targets such as BDNF.

    Ultimately, this results in reducing the numbers of fully functional GABAergic neurons postnatally and a concomitant increased susceptibility toward hyperexcitability. The delayed migration of GABAergic interneuron progenitors results in reduced gene expression postnatally which is likely the consequence of increased amounts of DNA methylation.

    The net effect of stress during early development is to disrupt the balance of excitatory/inhibitory neuronal firing due to the loss of function associated with disrupted neuronal migration and maturation.”

  • Prenatal nutrition:

    “Exposure to a wide range of environmental toxins that impact neurodevelopment also result in global DNA hypomethylation. This model was extended to connect pathways between dietary nutrition and environmental exposures in the context of DNA hypomethylation. More recently, this hypothesis was expanded to show how dietary nutrients, environmental toxins, genome instability and neuroinflammation interact to produce changes to the DNA methylome.”

  • Maternal infections:

    “Inflammation, autoimmunity and maternal immune activation have long been suspected in the context of aberrant neurodevelopment and ASD risk.”

  • Exposure to pollutants, medications, alcohol

This was a current review with many 2015 and 2014 references. However, one word in the reviewers’ vernacular that’s leftover from previous centuries was “idiopathic,” as in:

“Idiopathic (nonsyndromic) ASD, for which an underlying cause has not been identified, represent the majority of cases.”

It wasn’t sufficiently explanatory in 2015 to use categorization terminology from thousands of years ago.

Science has progressed enough with measured evidence from the referenced studies that the reviewers could have discarded the “idiopathic” category and expressed probabilistic understanding of causes. They could have generalized conditional origins of a disease, and not reverted to “an underlying cause has not been identified.”

Another word the reviewers used was “pharmacotherapeutic,” as in:

“The goal for the foreseeable future is to provide a better understanding of how specific genes function to disrupt specific biological pathways and whether these pathways are amenable to pharmacotherapeutic interventions.”

Taking “idiopathic” and “pharmacotherapeutic” together – causes for the disease weren’t specifically identified, but the goal of research should be to find specific drug treatments?

Of course reviewers from the Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago are biased to believe that “the design of better pharmacotherapeutic treatments” will fulfill peoples’ needs.

Are their beliefs supported by evidence? Without using drugs, are humans largely incapable of therapeutic actions such as:

  • Preventing epigenetic diseases from beginning in the prenatal environment?
  • Treating epigenetic causes for and alleviating symptoms of their own disease?

http://www.futuremedicine.com/doi/full/10.2217/epi.15.92 “Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder”

Telomere dynamics, stress, and aging across generations

This 2015 Pennsylvania/North Dakota animal and human review noted:

“The mechanisms linking stress exposure to disease progression and ageing either within individuals or across generations are still unclear, but recent work suggests that telomere dynamics (length and loss rate) may play an important role.

Parental stress may directly influence the parental germline telomeres pre-fertilization, affecting the telomere length inherited by offspring. Alternatively, parental stress may affect telomere dynamics indirectly either pre- or post-natally. The physiological mechanisms by which stress elicits changes in telomere length are also diverse.

We need more information about how these effects vary between developmental stages, among individuals, and within tissues of individuals..to mitigate the effects of early life adversity on human health.”

I was disappointed that the reviewers chose Problematic research with telomere length as a reference. Then again, maybe their statement:

“how these traits are related to one another clearly deserves more study”

is a polite way of saying that study’s methodology was flawed?

Regarding evolutionary biology:

“While most evidence suggests that the effect of parental stress exposure on offspring telomeres is negative, it is important to remember that this is just one trait that can contribute to parental and offspring fitness.

Investment in traits that increase fitness is expected to be favoured, even if they come at a cost to traits associated with longevity, such as telomere length.”

A similar point was made in a reference of A study of DNA methylation and age that:

“Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”


http://rsbl.royalsocietypublishing.org/content/11/11/20150396 “Telomere dynamics may link stress exposure and ageing across generations”

A review of epigenetic transgenerational inheritance of reproductive disease

This 2015 Washington review of epigenetic transgenerational inheritance of reproductive disease defined transgenerational effects as follows:

“In considering transgenerational phenomena it is important to distinguish between direct exposure effects versus germline (sperm or egg) mediated transgenerational events.

When a gestating F0 generation female is exposed the F0 generation female, the F1 generation fetus and the germ cell (sperm or egg) that is inside the fetus and that will produce the F2 generation are all directly exposed. Any effects in the F0, F1 and F2 generations may be due to direct exposure toxicity or to environmentally induced epigenetic changes in the directly exposed cells. Examination of the F3 generation (great grand-offspring) is needed to determine if a transgenerational phenomenon has occurred, since the F3 generation has had no direct exposure effects.

In contrast, in the event an adult male or non-pregnant female is exposed, the F0 generation adult and the germ cells that will generate the F1 generation are directly exposed, such that examination of the F2 generation (grand-offspring) is required to demonstrate a transgenerational phenomenon.”

This review was an example of a government agency commissioning science that narrowly supported their view. NIEHS funded this review, and the authors interpreted “environment” in “Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease” to fit this conduit of public funds.

The problem was that this interpretation of “environment” limited the subject to primarily JP8, Vinclosolin, Dioxin, plastics, and pesticides as pictured in the Venn diagram of the study’s last page. The authors’ tailoring of “environmentally induced” to the government agency’s interests should have similarly restricted the title.

Other interpretations of “environment” were in studies such as:

and their references. Such studies demonstrated both that:

  1. Environmental factors like stress and nutrition – especially in early life – cause diseases in later life; and
  2. These diseases may be inherited by the subjects’ descendants.

The authors elsewhere referred generally and specifically (nutrition) to studies of other environmental factors.

Have you ever heard that our children and then their children could possibly inherit our diseases caused by stressful environments? Wouldn’t that research be of equal to or greater importance in our lives than pesticides’ harmful effects?

http://www.bioone.org/doi/10.1095/biolreprod.115.134817 “Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease”