Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Sep 11;22(17):R753-61.
doi: 10.1016/j.cub.2012.07.008.

Evolution of neurodegeneration

Mark R Cookson  1
Affiliations
Review

Evolution of neurodegeneration

Mark R Cookson. Curr Biol. .

Abstract

A number of neurodegenerative diseases principally affect humans as they age and are characterized by the loss of specific groups of neurons in different brain regions. Although these disorders are generally sporadic, it is now clear that many of them have a substantial genetic component. As genes are the raw material with which evolution works, we might benefit from understanding these genes in an evolutionary framework. Here, I will discuss how we can understand whether evolution has shaped genes involved in neurodegeneration and the implications for practical issues, such as our choice of model systems for studying these diseases, and more theoretical concerns, such as the level of selection against these phenotypes.

PubMed Disclaimer

Figures

Figure 1
Figure 1. The pathology of Parkinson’s disease
The cartoon shows a simplified view of the main neuropathological events in Parkinson’s disease at three levels from left to right. At the level of the brain, a major pathway is degeneration of the dopaminergic projections from the substantia nigra (in black) to the striatum (in purple), both of which are in the midbrain underneath the cerebral cortex. At the level of substantia nigra, the neurons that form the presynaptic portion of this pathway are normally melanized and are easily identified by this pigment in control brains (upper panel). In contrast, the loss of neurons in this region is so substantial that the whole area becomes depigmented in Parkinson’s disease cases (lower panel). Of the few remaining cells, many show pathological changes including the accumulation of proteins and lipids in Lewy bodies. A characteristic protein in Lewy bodies is α-synuclein, which is encoded by the SNCA gene that increases the risk of PD.
Figure 2
Figure 2. The Synuclein family
The tree on the left of the figure shows that there are several synuclein homologues in many vertebrate species. These separate into three groups, identified as α-, β- and γ- synuclein and, interestingly, most species have one of each homologue. Exceptions to this general rule include species such as the lamprey and zebrafish, which appear to have evolved multiple γ- synuclein homologues but lack an α-synuclein homologue. On the right are ideograms of the proteins. The characteristic KTEGV repeats, the number of which vary between homologues are indicated in yellow. Mutations in α-synuclein, shown in red, are associated with autosomal dominant Parkinson’s disease and include three point mutations and multiplications of the whole SNCA locus (indicated by the horizontal line).
Figure 3
Figure 3. The LRRK family
Like the synucleins, there are at least two distinct branches of the LRRK family represented by LRRK1 (lower part of the tree) and LRRK2 (upper part of the tree) in vertebrate species. The invertebrate LRRKs form a group that sits between the two vertebrate LRRK homologues (see text). The distinction between the LRRK1 and LRRK2 orthologues includes differences at the N-terminal, where LRRK2 (upper ideogram) includes a series of repeat sequences that LRRK1 (lower ideogram) lacks. Other domains include the anykrin-like repeats (ANK), leucine-rich repeats (LRR), Ras of complex proteins (Roc) and C-terminal of ROC (COR), kinase and WD40 domains.
Figure 4
Figure 4. MAPT
MAPT, coding for the axonal microtubule binding protein tau, is found in most vertebrates and conservation generally follows the standard phylogenetic tree for these organisms, as shown on the left of this figure. There are many other microtubule binding proteins but for clarity, here I have shown the nearest group, which includes the dendritic microtubule binding protein MAP2. These are a separate group of proteins but again these follow the same phylogenetic pattern across species. The protein structure of the six known tau isoforms is shown on the left. These isoforms are generated by alternate splicing of exons 2 and 3 (in green in the ideograms) generating different numbers of amino terminal inserts (2N, 1N or 0N) and by splicing of exon 10, which generates one extra microtubule binding repeat (4R or 3R). A selection of the known exonic FTD mutations is shown in red. In orange are intronic mutations that change the splicing but not the amino acid sequence, numbered by nucleotide position relative to exon 10.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hardy J, Orr H. The genetics of neurodegenerative diseases. J. Neurochem. 2006;97:1690–1699. - PubMed
    1. Lill CM, Bertram L. Towards unveiling the genetics of neurodegenerative diseases. Semin Neurol. 2011;31:531–541. - PubMed
    1. Halliday G, Lees A, Stern M. Milestones in Parkinson’s disease--clinical and pathologic features. Mov. Disord. 2011;26:1015–1021. - PubMed
    1. Shulman JM, De Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol. 2011;6:193–222. - PubMed
    1. Gasser T, Hardy J, Mizuno Y. Milestones in PD genetics. Mov. Disord. 2011;26:1042–1048. - PubMed

Publication types

MeSH terms