Therapeutic targets for PD

As LRRK2 and alpha-synuclien are the two most important genes involved in the pathological manifestation of PD, these are the obvious two candidates which can be targeted for therapeutic purposes. The main approach would be to stop or slow the progression of the disease: and the best therapy possible would be complete reversal.

What are the aliases for LRRK2

LRRK2 is known by a host of other different names: both the gene of the gene product. The commonly used aliases for LRRK2 are:

* DKFZp434H2111 * Dardarin
* FLJ45829 * LRRK2_HUMAN
* PARK8 * RIPK7
* ROCO2

Where is LRRk2 located ?

If you have ever wondered where LRRK2 is found in the human chromosome:

Cytogenetic Location: 12q12

Molecular Location on chromosome 12: base pairs 38,905,085 to 39,051,869

In details:

The LRRK2 gene is located on the long (q) arm of chromosome 12 at position 12.

More precisely, the LRRK2 gene is located from base pair 38,905,085 to base pair 39,051,869 on chromosome 12.

What are your chances of inheriting PD

If any member of your family has a history of PD, it is highly probable that you might be predisposed to the disease. The gene which has created a buzz in the scientific community for its role in PD is LRRK2. It is a relatively new gene and lots of scientific research is being carried out now and information is pouring in at a constant pace.
The mutation which has been prominent is the G2019S mutation on the LRRK2 gene found in chromosome 12. The single-letter change in the DNA code dramatically increases a person’s odds of developing Parkinson’s from one or two in a hundred to as much as eight in 10. One recent study found that a person who inherits the mutation has a 28% chance of developing Parkinson’s by the age of 59, 51% by the age of 69 and 74% by the age of 79 (Healy et al. 2008, Lancet, 7, 583-590).

Sergey Brin affected by LRRK2

Google co-founder Sergey Brin has indicated that he is predisposed to PD through a family history and most probably the gene LKKR2 is involved in the same, with the mutation at G2019S.

http://news.cnet.com/8301-1023_3-10045958-93.html

LRRK2 in news

Recently the PD field and specifically the LRRK2 gene came into limelight. The co-founder of Google, Sergy Brin has been diagnosed with PD and preliminary results point out to the fact that there is a point mutation in G2019, where the Glycine residue has been mutated to Serine (S) [G2019S mutation]. This mutation has been linked with enhanced levels of kinase activity and is known to be effected in PD: both in familial (5-6%) and sporadic cases (1-2%).

Brin’s mother was diagnosed with Parkinson’s, and now he has to live with the reality that he might one day develop the disease as well. Says Brin:

Nonetheless it is clear that I have a markedly higher chance of developing Parkinson’s in my lifetime than the average person. In fact, it is somewhere between 20% to 80% depending on the study and how you measure. At the same time, research into LRRK2 looks intriguing (both for LRRK2 carriers and potentially for others).

This leaves me in a rather unique position. I know early in my life something I am substantially predisposed to. I now have the opportunity to adjust my life to reduce those odds (e.g. there is evidence that exercise may be protective against Parkinson’s). I also have the opportunity to perform and support research into this disease long before it may affect me. And, regardless of my own health it can help my family members as well as others.

I feel fortunate to be in this position. Until the fountain of youth is discovered, all of us will have some conditions in our old age only we don’t know what they will be. I have a better guess than almost anyone else for what ills may be mine — and I have decades to prepare for it.


Also more info available at:

http://thegenesherpa.blogspot.com/2008/09/lrrk2-and-parkinson-disease.html

http://news.cnet.com/8301-1023_3-10045958-93.html

LRRK2

LRRK2 (Leucine Rich Repeat kinase 2) is a cytoplasmic protein of 2527 amino acids. This protein is widely expressed in Substantia Nigra (SN) specially in the A9 Dopaminergic neurons (A9 DA). Other regions in the brain where LRRK2 has also been identified include cortex, hippocampus, straitum and cerebellum. Peripheral organs where the existence of LRRK2 has been detected include Heart, Placenta, Kidney, Lung, Skeletal Muscle, Pancreas etc. Subcellular localization of LRRK2 is observed in Golgi, Mitochondira and endosomal vesicles.

As a protein, LRRK2 has both GTPase activity and kinase activity encoded by the same molecule. This is one of the very few proteins found in the human genome which has both the activities in the same gene. The kinase function of LRRK2 has been of utmost importance in PD as it has been observed that enhanced kinase activity of LRRK2 mutants (G2019S, R1441C) leads to neurodegenation and cell death. The kinase domain has reasonale sequence homology to MLK (Mixed Lineage Kinase) subfamily of MAPKKK proteins. How does PD-associated mutant LRRK2 deviate from normal function remains to be elucidated in detail which will in turn help us deduce the normal function of LRRK2 in brains.

alpha-synuclien and LKKR2 in PD

The two most significant genes which have been widely implicated in familial and sporadic PD are the alpha-synuclein (ASN) and Leucine Rich Repeat Kinase 2 (LRRK2). In PD patients with defects in either of gene (through mutation or other disease causing mechansim), evidence of Lewy Bodies (intracellular esinophillic depositions) and Lewy Neurites are observed in the substantia nigra (SN) of the brain.
PD has been the second most common neurodegenerative disease in the world affecting about 2% of the population. It is a neurological disorder in which degeneration of midbrain dopaminergic neurons leads to loss in motor functions.
I would like to define the cardinal symptons of PD as some one who has been "TRAP"-ed by old age:
T: Tremor
R: Rigidity
A: Akinesia / Bradykinesia
P: Postural Instability

Will discuss more about LRRK2 (the gene of my interest) in subsequent posts, and will evolve a link how GPCRs play a role in PD.