Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS) are all incurable neurological diseases; each carries a range of symptoms, and various short-term treatments to reduce their respective severity. The ongoing search for solutions to these devastating diseases is complicated by minimal overlap in symptomology. The absence of similar symptoms seems to indicate that each aliment has a distinct origin. However, recent findings highlight one increasingly important factor: a toxic protein build up in the brain that kills surrounding neurons.

Proteins are constructed when hundreds of smaller amino acids are strung together through translation. Translation uses the genetic information represented on strand of RNA to build long chains of amino acids. The resulting chains form complex three dimensional shapes, proteins, which perform a variety of functions including transportation and antibodies. These three predominant neurological disorders feature a common protein dysfunction factor (e.g. alpha-synuclein, beta amyloids, and FUS proteins). Their apparent dysfunction leads to the destruction of neural networks.

Alzheimer’s disease is a chronic neurodegenerative condition that occurs in more than half of all cases of dementia. Symptoms include loss of short-term memory, inability to create new long-term memories, and a fifty percent decrease in brain density. Alzheimer’s exhibits a buildup of beta-amyloid proteins into amyloid plaques. Beta-amyloid does not have a set structure, which allows the formation of soluble oligomers. The normal function of the protein is to enrich the neuron by congregating in the axon. If the protein folds into an improper oligomeric form it becomes intensely toxic to the cell. This prompts a period of depolarization and cell death via excitotoxicity. Other cells may accidently absorb free beta-amyloid, which leads to a similar demise. Bloom, Naussbaum, and Seward map the most common way the beta-amyloid plaques spread through the brain, beginning in the basal temporal cortex, expanding outward to the hippocampus and eventually the neocortex.

Unfortunately, there is no treatment plan for dispersing the buildup of plaques in the brain. However, recent developments offer artificial means to boost the enzymes responsible for clearing beta-amyloid plaques. This method holds the potential to reverse or even prevent the realization of early Alzheimer’s disease.

(FIG.I) The Beta-Amyloid protein is a hallmark of Alzheimer’s Disease.

Parkinson’s is another chronic neurodegenerative disorder. It causes tremor in the hands, stooped posture, impaired movements, and the loss of automatic movements (e.g. blinking or arm motions while walking).The protein relevant to Parkinson’s is alpha-synuclein, most commonly observed in an impossibly entangled form in Lewy bodies. It is primarily found in the presynaptic areas of neurons, and is likely involved in the maintenance of synaptic vesicles full of neurotransmitters. Like the buildup of beta-amyloid plaques in Alzheimer’s, a distorted form of alpha-synuclein is toxic to the neuron. These can aggregate and prevent the release of neurotransmitters into the synapse, specifically the neurotransmitter dopamine.

Misfolded alpha-synuclein is also the primary component in the buildup of Lewy bodies in the substantia nigra, though it is currently unclear to what degree this affects the progression of Parkinson’s disease.

Two drug treatments focusing on alpha-synuclein are currently in clinical trials. One drug is meant to prevent the protein build up, while the other attempts to disperse the toxic proteins after their formation.

(FIG.II) Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer’s disease.

Amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig’s disease, is a progressively fatal illness that attacks the spinal neurons responsible for voluntary and involuntary movement. Eventually the upper and lower motor neurons that govern movement die or fail to depolarize. The resulting muscle atrophy causes complete loss of control of voluntary movement. There is no definitive cause of ALS, but researchers at the University of Toronto recently proposed a possibility. They postulate that ALS originates in the buildup of dysfunctional proteins, but more subtly than anticipated.

The protein, Fused in Sarcoma (FUS), normally participates in the function of a spinal column neuron. Unlike other non-structured proteins such as beta-amyloid (associated with Alzheimer’s) or alpha-synuclein (associated with Parkinson’s), the structure of FUS can change between gel and liquid. The gel form collects RNA fragments, transporting them to an area of the cell where they can be used to make new proteins.

Researchers found that a mutation to the FUS causes it to form a harder gel-like substance, less willing to relinquish RNA fragments. This prevents the cell from forming life-saving structures that it requires. Researchers intend to utilize this discovery to slow the development of ALS and extend the average patient life-expectancy to more than five years after diagnosis.

(FIG.III) FUS aggregates (green) in cultured cells expressing a mutant form of protein.

Alzheimer’s, Parkinson’s, and ALS seem superficially different. However, their underlying biological mechanisms all display a malfunctioning protein resulting in cell death. All of these proteins feature a subtle change in their formation that fundamentally alters their function within the cell. This essentially renders the protein poisonous. More comprehensive data on protein dysfunction origins, and the translation from RNA could transform our understanding of neurological disorders. Moving forward similar research has the potential to expand into other fields that explore conditions such as Schizophrenia or Autism.

• Beta-amyloid are made of 36–43 amino acids that form the main component of the amyloid plaques in Alzheimer’s disease. These proteins form flexible soluble oligomers that can exist in several different forms.
• Alpha-synuclein is found throughout the body and is most prominently used near the presynaptic terminals of neurons. It is made of 140 amino acids, and is believed to regulate the release of dopamine in the brain.
• FUS is responsible for gathering fragments of RNA and bringing them to the mechanisms to create the life-saving proteins to maintain cell function. FUS is unique for its ability to change between a gel and a liquid like form enabling it to relinquish RNA fragments.

Image Credit

• (Featured Image) “From DNA to Protein: The synthesis of RNA from DNA is called transcription (the DNA is transcribed into RNA). In this figure, the RNA is being synthesized from the red strand of DNA and then translated into protein.” from DNA, RNA and Protein – The Central Dogma [2017. Science Explained]
• (FIG.I) “Images across the top show compilations of PET brain scans of people who are cognitively normal. Images across the bottom show compilations of PET brain scans of patients with symptoms of mild Alzheimer’s disease. Photo: Mathieu Brier / Washington University” from New brain imaging agent is marker for progression of Alzheimer’s [2016-05-13. Sandra Levy, MedCity News]
• (FIG.II) “Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer’s disease.” from Anti-SNCA / Alpha-Synuclein Antibody (clone 3H9) LS-C204586 [2017-08-21. Science Explained]
• (FIG.III) “FUS aggregates (green) gradually develop in cultured cells expressing a mutant form of protein” from MND Research Blog [2017-06-06. Motor Neurone Disease Association]

References

1. FUS: FUS RNA binding protein [2016. U.S. National Library of Medicine]
2. SNCA: synuclein alpha [2016. U.S. National Library of Medicine]
3. DNA, RNA and protein – the Central Dogma [2015. ScienceExplained]
4. Two More Alpha-synuclein Drugs in Clinical Trials [2015-08-14. Maggie McGuire Kuhl. michaeljfox.org]
5. Diseases and Conditions: Parkinson’s disease [2015-07-07. Mayo Clinic Staff. mayoclinic.org]
6. Promising New Alzheimer’s Drug Validates Anti-Amyloid Approach [2015-03-23. curealz.org]
7. Amyotrophic Lateral Sclerosis (ALS) Fact Sheet [2013-06. nih.gov]
8. Possible new explanation for ALS [2015-10-29. University of Toronto. eurekalert.org]
9. Alzheimer disease: A tale of two prions [2012-09-10. George S. Bloom, Justin N. Nussbaum, Matthew E. Seward. Prion]
10. Researchers Discover Underlying Cause of Lou Gehrig’s Disease [2011-08-22. Meredith Melnick. Time]
11. Clinical Review: Alzheimer’s disease [2009-02-05. Alistair Burns, Steve Iliffe. BMJ]

Related Posts

• Autism Breakthrough [2014-08-24. Jacquelynn Kelly. MMRF/Groundwork]
• Understanding ALS [2014-08-21. Jacquelynn Kelly. MMRF/Groundwork]
• Neurology: Memory Restoration Research [2014-07-25. Jacquelynn Kelly. MMRF/Groundwork]
• Alzheimer’s blood test shows early detection potential [2014-05-30. MMRF Staff. MMRF/Groundwork]