The following questions give insightful information obtained from the article Ancient origin of the Parkinson disease gene LRRK2

1. Based on our discussion of paralogous genes in class, how do you think the Roco family of genes originated?  Do we see deep homology in this gene family?  How do you know?

Although the majority of organisms that have LRRK genes from the Roco family are vertebral deuterostomes, protostomes lacking vertebrae have also been shown to have genes that are paralogous to the ones in more complex deuterostomes, including humans.  The fact that these genes exist, but in simpler form, in organisms that came earlier in our evolutionary history shows a close linkage of this family of genes in a wide range of species.  One species in particular, the sea anemone Nematostella vecentis, a cnidarian organism, showed to have the most complex set of LRRK genes described in any animal, thus far.  This species is ancient and these genes must have developed long ago in its evolution.  Also, the LRRK2 gene of N. vecentis is an exact paralog to the human LRRK2 gene, showing direct evolutionary linkage between the two.  A very simple form of a Roco gene – containing a Roc, COR, and Kinase domains – must have first formed in protostomes closely related to N. vecentis and through the process of gene duplication errors during meiosis, must have created several forms of these types of genes, similar to the evolution of the hemoglobin paralogous gene family.

Because we see forms LRRK and other Roco family genes in all vertebrate deuterostomes, as well as some protostomes, such as insects, the origins of this gene family must extend far back in the evolutionary timeline.  The existence of this gene family in both highly organized, complex vertebrates, as well as simpler, less complex non-vertebrates shows both deep homology and an ancient origin of the gene family.

2. According to the author, are the LRRK2 genes in humans and sea anemones orthologous? In figures 3 & 4, are the LRRK2 genes from these two species in the same clade?

Species are orthologous when they are different but evolve from a common ancestral gene. When researching the genome of Cnidarians, the author saw the relationship between the human and sea anemone LRRK2 genes. Although the LRRK2 gene was at first thought to have arrived through duplication, it was later discovered that the LRRK2 gene was one of two duplications that occurred before the protostome-deuterostome split. Because of the two duplications, LRRK1, LRRK2, and LRRK3 genes were now produced. Vertebrates retained the LRRK1 and LRRK2 gene while protostomes only had the LRRK3 gene. All three genes were present in Cnidarians, sea anemones, starfish, and Echinoderms. In figure 3 and 4 it can be seen that the LRRK2 genes from both Homo sapiens and Nematostella Vectensis are found in the same clade. 

3. Both types of PD (familial and sporadic) involve the human LRRK2  gene. Differentiate between these two types and briefly discuss the role of LRRK2 in each.

Individuals with Familial Parkinson’s have a history of the disease in their family. On the other hand, Sporadic Parkinson’s disease occurs randomly and does not seem to run in families. Sporadic Parkinson’s disease is the more common form. Both types of Parkinson’s Disease involve the human LRRK2 gene. It was found that dominant mutation in LRRK2 may explain 13% of the familial PD cases and 5% of the sporadic PD cases. It has been found that LRRK2 orthologs have an Arm-like surface. Researchers have found that mutations in this surface have been involved in familial PD.  In both Sporadic and Familial Parkinson’s Involvement of LRRK2 gene is believed to play a role in dopaminergic cell death and the onset of the disease. In previous studies on non-human subjects the loss-of-function mutations in LRRK2 is what leads to dopaminergic cell death. It is unknown if this is the case for humans as well. This study suggests that increased/constitutive activity of the LRRK2 protein (probably through increased kinase function) is what leads to the loss of dopaminergic cells in patients with PD.  

4. Is it parsimonious for the author (page 10-11) to assume that LRRK3 was present in all eumetazoans and then lost in vertebrates?  What would be an alternative hypothesis?

Parsimony is the principle which tells us to choose the simplest scientific explanation that fits the evidence we have collected. And in the terms of looking at phylogenic tress, the best hypothesis is the one that requires the fewest evolutionary changes. When looking at Figures 3 and 4, we can address the question of which phylogenic treat is more parsimonious. In Figure 3, LRRK3 diverges earlier on from what would later end up being LRRK1 and LRRK2. This demonstrates the author’s belief that the LRRK3 gene was maintained in cnidarians, echinoderms, and protostomes, but it was lost in vertebrates. In Figure 4, however, LRRK2 diverges early to leave LRRK3 and LRRK1 to break away from each other at a later point. This shows another hypothesis which is that the LRRK3 gene is eventually lost in both the LRRK1 and LRRK2 genes. To determine which hypothesis was the better fit, we looked at the least complicated phylogenic tree with the fewest evolutionary changes. For Figure 3 and 4, although both possible, Figure 3 was the most parsimonious. But with the work of any phylogeny, more work could be performed to add more extension to the trees, creating a better, more parsimonious outcome about how these genes correspond with one another.

5. Why is it important to study protein folding/misfolding in Parkinsons, even though we know the genes that are responsible? 

            Studying the effects of protein folding are extremely important, even though we already know the cells that are affected by Parkinson’s Disease (LRRK1 & LRRK2). There is increasing evidence that states Parkinson’s, Alzheimer's , and even Huntington’s may all have a common root to the problem, protein folding. If the proteins do not fold into the correct shapes, they disrupt cellular function (whatever that may be) and cause clumps. In each disease they are called something different but for Parkinson’s Disease, they are called “Lewy bodies”. Studying the protein folding has many applications such as better explanations of how the disease starts, worsens, or spreads, as well as different treatment strategies based on the misfolded proteins.

         Looking at Mad Cow Disease, may better lead to our understanding of how these misfolded proteins can spread throughout the brain. For people with MCD, they have little bodies called prions which go around misfolding every protein that it comes in contact with. If Parkinson’s or Alzheimer’s has a similar mode of spreading to other cells, it would explain why these diseases are progressively degenerative in nature. Thinking about how the proteins fold can give us new methods of treatment, as well as an opportunity to continue uproot the cause of these neurodegenerative diseases.