Progress and Prospects in Parkinson's Research/Causes/Inheritance/SNCA

The SNCA_gene has been implicated in the onset of some types of familial Parkinson’s Disease.

BackgroundEdit

Its official Full Name is “Synuclein, alpha (Non A4 Component of Amyloid precursor)”.

Like many other genes, SNCA is known by more than one name. Alternative names are:

  • PD1 = Parkinson’s Disease 1
  • NACP = Non-Amyloid Component of senile plaques Precursor protein)
  • PARK1
  • PARK4

In the human genome SNCA is to be found on the long arm of chromosome 4.

The cytogenetic location is 4q21.

The molecular base pairs are from 90,645,249 to 90,759,446.

The PD Gene database (2011) [1] lists 49 Polymorphisms for this gene, of which 39 are termed ‘Significant’. It also cites 103 Caucasian gene association studies, 18 Asian gene association studies and 4 Family-based studies.

What does SNCA do?Edit

In a healthy brain SNCA provides instructions for the production of a protein called Alpha Synuclein. This protein is abundant in the brain, where it is found in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum. Smaller quantities are also found in muscles and in the heart.

In the brain, alpha synuclein is found mainly at the tips of nerve cells in structures called presynaptic terminals. Here it interacts with fats and other related proteins. The role of the presynaptic terminals is to release neurotransmitters from compartments known as synaptic vesicles.

Much has still to be learned about the precise function(s) of alpha-synuclein. There are indications that it has a role in maintaining a supply of synaptic vesicles for the presynaptic terminals. It may also help regulate the release of dopamine in dopaminergic neurons.

It has also been found in neuronal mitochondria by Zhang et al (2008) [2] and Liu et al (2009) [3] Alpha-synuclein is highly expressed in the mitochondria in the olfactory bulb, hippocampus, striatum, and thalamus. It is suggested that alpha-synuclein in mitochondria is differentially expressed in different brain regions and the background levels of mitochondrial alpha-synuclein may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration.

Alpha-synuclein is specifically upregulated in a discrete population of presynaptic terminals of the brain during a period of acquisition-related synaptic rearrangement. It has been shown by Alim et al (2002) [4] that alpha synuclein significantly interacts with tubulin, and by Alim et al (2004)[5] that alpha-synuclein may have an activity as a potential microtubule-associated protein like tau

What is the effect of mutations?Edit

At the moment the effects of SNCA mutations have been classified into two types.

One type of alteration changes one of the protein building blocks (amino acids) used to make alpha synuclein. In some cases, the amino acid alanine is replaced with the amino acid threonine at protein position 53 (written as Ala53Thr) or with the amino acid proline at position 30 (written as Ala30Pro). In a few cases, the amino acid glutamic acid is replaced with the amino acid lysine at position 46 (written as Glu46Lys). These mutations cause the alpha synuclein protein to misfold, or take on an incorrect 3-dimensional shape, which renders it ineffective.

In the other type of alteration, one of the two SNCA genes in each cell is inappropriately duplicated or triplicated. Instead of the normal two copies of the SNCA gene, each cell has three or four copies, which leads to an excess amount of alpha synuclein.

Mutated or excess alpha synuclein proteins may cluster together to form oligomers and impair neuronal functions in specific regions of the brain. For example, aggregated alpha synuclein may disrupt the regulation of dopamine, which allows dopamine to accumulate to toxic levels and eventually kill the nerve cell. Researchers also suspect that the resultant misfolded or excess alpha-synuclein shuts down the cell machinery that removes unwanted proteins. Unwanted proteins may then clog the cell and impair neuron functions.[citation needed]

Misfolded alpha-synuclein is also a major component of Lewy bodies. These are abnormal deposits that appear in certain nerve cells in the brain. Lewy bodies in a region of the brain called the substantia nigra, which provide the neurotransmitters that control balance and movement, are a characteristic feature of Parkinson's disease.

Is it associated with other diseases?Edit

Two mutations cause a particular disorder known as Dementia with Lewy bodies. The symptoms typically include dementia, visual hallucinations, fluctuations in attention, and changes characteristic of Parkinson’s disease such as trembling or rigidity of limbs, slow movement, and impaired balance and coordination.

One of the SNCA mutations responsible for dementia with Lewy bodies replaces the amino acid glutamic acid with the amino acid lysine at position 46 in the alpha-synuclein protein (written as Glu46Lys). The other mutation, which replaces the amino acid alanine with the amino acid threonine at position 53 (written as Ala53Thr), is associated with the features of both Parkinson's disease and dementia with Lewy bodies.

ResearchEdit

The SNCA gene continues to generate a considerable amount of research interest because:

  • It was the first gene to demonstrate a genetic link to PD;
  • There is a considerable body of gene association data to draw on;
  • It codes for the alpha-synuclein protein, which has been shown to be significantly involved in the pathogenesis of the disease.

Two pieces of ongoing research are of note.

Rogers, Jack T (2009) [6] of Massachusetts General Hospital is currently engaged in the search for a novel therapy involving SNCA. Ongoing clinical trials are taking place in conjunction with the treatment of Alzheimer’s Disease of a drug called Posiphen. This acts upon the SNCA gene and serves to block the production of alpha synuclein. The researchers plan to extend this trial to test the drug’s efficacy as a treatment for SNCA-related Parkinson’s Disease.

SNCA has also been implicated in the onset of a Parkinson plus condition called Multiple System Atrophy. Currently there is no easy was of distinguishing between the two conditions. Scholz, Sonia W. and Mhyre, Timothy R. (2010) [7] of Georgetown University are conducting a detailed comparison of the pathology of the two conditions with a view to defining the associated therapeutic targets.

Further readingEdit

OMIM entry

PD Mutations Database

Leiden Open Variation Database

Today

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Related PagesEdit

<Back to Causes > Inheritance

Sub Pages:

SNCA - LRRK2 - MAPT - GBA - HLA

ReferencesEdit

  1. (1) http://www.pdgene.org/meta.asp?geneID=226
  2. Zhang, L.; Zhang, C.; Zhu, Y.; Cai, Q.; Chan, P.; Uéda, K.; Yu, S. and Yang,H. (2008)Abstract“Semi-quantitative analysis of alpha-synuclein in subcellular pools of rat brain neurons: an immunogold electron microscopic study using a C-terminal specific monoclonal antibody,” Brain Research 1244 40-52. http://www.ncbi.nlm.nih.gov/pubmed/18817762
  3. Liu, G,.; Zhang, C.; Yin, J.; Li, X.; Cheng, F.; Li, Y.; Yang, H.; Uéda, K.; Chan, P. and Yu, S. (2009)Abstract Neuroscience Letters 454 (3) 187-192.“Alpha-synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity,”http://www.ncbi.nlm.nih.gov/pubmed/19429081
  4. Alim, M. A.; Hossein, M.S.; Arima, K.; Takeda, K.; Aizawa, T.; Izuriyama, Y.; Nakamura,M.; Kaji,H.; Shinoda,T.; Shinichi, H. and Kenji,U. (2002) Full Text Journal of Biological Chemistry 277 (3) 2112 -2117. Tubulin Seeds α-Synuclein Fibril Formation, http://www.jbc.org/content/277/3/2112.long
  5. Alim, M.A.; Ma, Q.L.; Takeda, K.; Aizawa, T.; Matsubara, M.; Nakamura, M.; Asada, A.; Saito, T.; Kaji, H.; Yoshii, M.; Hisanaga, S. and Uéda K. (2004) Full TextJournal of Alzheimer’s Disease 6(4) 435-442; discussion 443-449. Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein, http://www.ncbi.nlm.nih.gov/pubmed/15345814
  6. http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGrants_3.cfm?ID=584
  7. http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGrants_3.cfm?ID=681