Genomics: Insight

Research Question: What impact do epigenetic factors have on neurodegenerative diseases and are there any interventions that an individual can do to reverse or slow this process? 

Epigenetic factors are molecular changes in gene expression without alterations of the actual DNA code. The study of epigenetics works to differentiate phenotypes explaining how each function is unique to its process, despite having the same identical genetic information¹. Epigenetic mechanisms may involve multiple processes including chromatin remodeling, DNA methylation, and histone modification. All of these work together to influence patterns in gene expression that are essential for normal cellular functions. 

What’s the purpose? In this paper we will explore the roles of epigenetics and what impact it has on neurodegeneration. By comparing normal age-related cognitive decline with neurodegenerative conditions, we can better understand how certain cellular factors contribute to the development of neurodegenerative health issues as we age. For example, according to Culig et al., just simply adding years to one’s life overall doesn’t improve the quality of life if you have significant cognitive dysfunction from conditions such as Parkinsons or Huntington's¹. They equated the impact of early cognitive decline to someone having a premature death. Likewise, we all look forward to being able to age naturally with healthy brain functions, so we all can live to our fullest potential. The latest surge in epigenetics research shows how neural reprogramming has improved our potential ability to mitigate neurodegenerative symptoms related to aging. With this, we aim to enhance not only our longevity but also the health of both our body and brain.

What is Neurodegeneration and how does epigenetics relate to it?      

Neurodegeneration refers to the progressive decline in motor and cognitive functions resulting from the dysfunction, damage, and loss of neurons. This process involves the deterioration of cellular structures, such as axons, dendrites, and synapses, as well as a reduction in the overall number of neurons. It also encompasses the disruption of neural networks that are crucial for communication between different brain regions. As neurons degenerate, their ability to transmit signals efficiently is compromised, leading to the gradual loss of essential brain functions. This phenomenon is commonly associated with diseases such as Alzheimer's and Parkinson's, where both genetic and environmental factors contribute to the acceleration of neuronal damage. Similarly, in (ALS) Amyotrophic lateral sclerosis, there is loss of motor neurons from both the spinal cord to the brain (Table 1)². Many believe that there are likely early alterations in cellular functions that stem from epigenetic changes such as histone modifications and DNA methylation patterns. According to Sharma et al., some damage in chromatin rearrangement and DNA are specifically related to multiple proteins such as: RNA binding protein/TAR DNA, (APP) a-synuclein protein and b-amyloid precursor protein, (FUS) fused in sarcoma, (TDP-43), and lastly (SOD1) superoxide dismutase 1 (All summarized in Table 1)³.  While these proteins don't play a direct role in modifying chromatin or DNA, if they are damaged, it does contribute to epigenetic dysregulation and instability. 

Furthermore, with a significant increase in both the aging and neurodegenerative populations, it has been a wake up call for the demand for more research related to potential therapies that can ease various ageing related neurodegenerative symptoms such as cognitive decline, loss of motor coordination, memory loss, disorientation, and even slowing down the process of neurodegenerative diseases. In a journal review article from Singh et al.,  from Jawaharlal Nehru Centre for Advanced Scientific Research in Bangalore, India, they noted that the modification of chromatin plays a big role in the formation of neurological diseases and a therapy that can possibly target this is miniature molecular modulators which are low molecular weight organic compounds that regulate biological processes by targeting and interacting with targets such as proteins, receptors, or enzymes. This fixates on the specific disease related epigenetic pathways (As mentioned for example: Parkingsons, Alzeihmers etc.)⁵. Now through the use of epigenetic reprogramming in our cellular processes, we can work towards ameliorating both brain activity and restoring the original gene expression. 

Looking deeper into Epigenetics, changes can occur at different levels including during DNA methylation, histone acetylation/methylation, and chromatin remodeling. DNA methylation is an epigenetic mark inherited through the transfer of a methyl group. DNA methylation silences promoters or enhancers involved in gene expression and depending on whether it’s histone acetylation/methylation, this works to either increase/decrease transcription levels. (DNA methylation controls turning on/off gene expression and histone acetylation is an expression level regulator) Additionally, chromatin remodeling opens a cell’s chromatin in the nucleus so gene expression can take place. All these processes are done to control where, what and how much genes are expressed which can create epigenetic changes.  Aging is related to these changes as when someone ages the functions of the body begin to fail and have age-related diseases such as neurodegeneration⁶.

As for how these epigenetic changes affect the longevity of a healthy constitution, there is a link between genotype and phenotype which can be seen through how epigenetic changes (the genotype) can affect the phenotype (the aging processes). To start off, with DNA methylation there are higher expressions of methylation in skeletal muscles of aged individuals. There are different DNA methyltransferases or DNMTs (DNMT1, DNMT3A, and DNMT3B) which are responsible for gene silencing. DNMT1 decreased with age with a decrease in DNA methylation level but mutant DNMT1 are shown to degeneration neurons⁶. DNA methylation usually decreases with age, mainly observed in mouse and human tissues like the small intestine, liver, and brain. Another variable that may increase methylation are age-associated variably methylated positions or aVMPSs and age-associated differentially methylated positions or aDMPs which are a type of CpG sites which increase methylation with age. aVMPs come from the downregulation of pentose metabolism genes (PYGL, TALD01, and PGD). 

Similarly, histone methylation and acetylation influence lifespan. Histone methylation has four important markers: H3K4me3, H3K27me3, H3K36me3, and H3K9me3. H3K4me3 with age have been known to accumulate in regions such as ASH-2 trithorax complex and ROS stimulation in mice which are associated to influence lifespan.  H3K27me3 levels increase in mice but there is a variability in species. H3K36me3 is known to shorten lifespan in yeast and H3K9me3 changes heterochromatin function in aging cells. Histone acetylation, linked to longevity through sirtuins which are a family of NAD+-dependent histone deacetylases (HDACs), are associated with aging due to SIRT1 levels decreasing in age. Other crucial regulators and sirtuins are: SIRT6, the balance between HATs and HDACs, CBP-1, H3K9ac and H3K27ac levels. Overall, chromatin structure including histone modifications and structural remodeling of chromosomes greatly influences aging while the structural remodeling mutations such as in H1 can lead to premature aging. Histone-modifying enzymes and ATP-dependent chromatin-remodeling complexes can alter nucleosomes which impairs chromatin structures⁶. Disruption in chromatin building, heterochromatin loss, and any changes in transcription also can contribute to the aging process. 

Numerous studies link epigenetic modifications to neurodegenerative diseases. For example, Huntington’s Disease (HD) is caused due to mutations in the Huntington (HTT) protein that is found in various tissues. A lot of DNA damage was found in brain samples of HD patients along with an increase in histone methylation. While improving longevity sounds like science fiction there are numerous interventions. One example of aging-intervention strategies are epigenetic regulators which are mechanisms that turn genes on or off during transcription (which were what we talked about earlier on DNA methylation, histone modification, chromatin remodeling)⁶.

To conclude, epigenetics is at the forefront of research for neurodegenerative diseases which can offer solutions and hope to the thousands of patients that are still affected to this day. The good and bad thing about epigenetic changes is that they are influenced by genetic predispositions and cellular factors which can make it difficult to find a complete prevention, but upcoming therapies do provide treatments to slow/reverse negative neurodegenerative symptoms. Overall with more research being done, epigenetics now holds the power to look for cures in the DNA itself and determine the way a gene is regulated. 

References

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