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Cellular changes due to LRRK2 parkinsonism - Parkinson's disease is a progressive, disabling, age-associated

neurological disorder with no known cure. Several genes have been identified as causing Parkinson's disease,

although mutations in leucine-rich repeat kinase2 (LRRK2) are by far the most common. The studies we propose

will identify the cellular proteins that interact with LRRK2 to cause Parkinson's disease. These proteins may be

amenable to future therapeutic manipulation.

Cellular effects of glucocerebrosidase (GBA) mutations in Lewy body diseases - Approximately 1 in 100 people

are carriers of mutations in the glucocerebrosidase (GBA) gene and are at considerably greater risk of diseasescharacterised clinically by parkinsonism and by the presence of Lewy body-related pathology. This study will

provide tissue-based evidence of the cellular lipid and protein changes relating to Lewy body formation in patients

with GBA mutations, providing the information necessary to identify the pathways and mechanisms involved.

In particular, a type of glial cell called microglia tries to clear an abnormal accumulation of a protein in the brain

called alpha-synuclein. The accumulation of this protein is typical in Parkinsons disease.

The microglia can actually consume the debris to get rid of it, but we think thats where the problem starts, says

Ms Stevens. Eventually, the volume of protein becomes too much for them and they become dysfunctional,

increasing in number and releasing toxic inflammatory factors uncontrollably. They lose the ability to regulate

their inflammatory response, which is what we think causes the ongoing neuronal death in Parkinsons disease.

The significance of this review, says Ms Stevens, is that it reveals the greater role of glial cells in Parkinsons

disease, and the need to investigate this role further, particularly in the earliest disease stages.

If we don't address these early glial changes, we're not really going to have any success in stopping neuronal

death, says Ms Stevens.

This research also supports the suggestions that anti-inflammatory drugs possibly targeting glial cells may

make an effective treatment for the disease.

technique is sensitive enough to provide an index of pre-clinical PD.

Leucine-rich repeat kinase 2 and alternative splicing

in Parkinson's disease.Elliott DA,Kim WS,Gorissen S,Halliday GM,Kwok JB.

Source

Neuroscience Research Australia, Barker St., Randwick, Sydney, NSW 2031, Australia.

Abstract

Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause

of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize

that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes.

Methods used in this study included western blotting analysis of subcellular protein fractions, exon-

array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors,

and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and

postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold; P

= 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array

analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with

nuclear (P < 10(-22) ) and cell-cycle functions (P < 10(-15) ). We replicated changes in gene

expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in

the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of

microtubule-associated protein tau (1.7-fold; P = 0.001) and exon 5 of the alpha-synuclein (SNCA)

gene (1.6-fold; P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes

associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with

decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing

of SNCA (1.9-fold; P < 0.001) and DST genes (log(2) 2.3-fold; P = 0.005) was observed in a cohort of

http://www.ncbi.nlm.nih.gov/pubmed?term=Elliott%20DA%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Elliott%20DA%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Kim%20WS%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Kim%20WS%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Kim%20WS%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Gorissen%20S%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Gorissen%20S%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Gorissen%20S%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Halliday%20GM%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Halliday%20GM%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Halliday%20GM%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Kwok%20JB%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Kwok%20JB%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Kwok%20JB%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Kwok%20JB%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Halliday%20GM%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Gorissen%20S%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Kim%20WS%5BAuthor%5D&cauthor=true&cauthor_uid=22528366http://www.ncbi.nlm.nih.gov/pubmed?term=Elliott%20DA%5BAuthor%5D&cauthor=true&cauthor_uid=22528366

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PD, compared with neurologically healthy, brains. This suggests that aberrant RNA metabolism is an

important contributor to idiopathic PD.

AbstractThe identification of the widespread deposition of fibrillized -synuclein in Lewy bodies and Lewy

neurites in the brains of patients with Parkinson'sdisease in 1997 has had a profound impact on how

the disease is now conceptualized. The previous focus on the loss of the dopaminergic nigrostriatalsystem, the concept of subcortical dementia, and the idea that Parkinson's disease was dominated by

motor impairment have all given way to research assessing more diverse brain regions, clinical

symptoms, and phenotypes. It is now recognized that Parkinson's disease is more than just a loss of

midbrain dopaminergic neurons in association with Lewy bodies. There are now several theories on

how the disease develops and progresses currently being validated in a variety of studies, although

many of these theories have yet to incorporate the phenotypic clinical and pathological changes

associated with age. A particularly exciting new area of research involves the cell-to-cell transmission

of pathogenic proteins. The recent consensus definition of Parkinson's disease dementia will allow its

pathologic substrates to be determined. These advances have progressed to a stage where the

preclinical stages of Parkinson's disease and its specific signs and symptoms are being predicted and

tested clinically. Such strategies herald a future wave of preventive strategies for Parkinson's disease

and its clinical symptoms.

Indices of oxidative stress in Parkinson's disease,Alzheimer's disease and dementia with Lewy bodies.Owen AD,Schapira AH,Jenner P,Marsden CD.

Source

Neurodegenerative Disease Research Centre, King's College, London, United Kingdom.

Abstract

The cause of neuronal cell death in Parkinson's disease is unknown but there is accumulatingevidence suggesting that oxidative stress may be involved in this process. Current evidence showsthat in the substantia nigra there is altered iron metabolism, decreased levels of reduced glutathioneand an impairment of mitochondrial complex I activity. However, these changes seem to be unique tothe substantia nigra and have not been found in other areas of the brain known to be alteredin Parkinson's disease, such as substantia innominata. In addition they do not appear to be related to

theLRRK 2

Damage to the LRRK 2 gene is the most common known cause for idiopathic parkinsonism,accounting for up to 5-7% of cases with a family history [1]. The most common mutation of this geneis autosomal dominant and results in an altered kinase activity and might influence the function of theouter mitochondrial membrane [8]. Patients withLRRK 2 involvement typically experience middle tolate disease onset and demonstrate classic parkinsonian symptoms [1].

presence of Lewy bodies, as other areas of the brain containing Lewy bodies do not show

http://www.ncbi.nlm.nih.gov/pubmed?term=Owen%20AD%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Owen%20AD%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Schapira%20AH%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Schapira%20AH%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Schapira%20AH%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Jenner%20P%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Jenner%20P%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Jenner%20P%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Marsden%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Marsden%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Marsden%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://pt851.wikidot.com/parkinsons-disease-cell-biology#LRRKhttp://pt851.wikidot.com/parkinsons-disease-cell-biology#LRRKhttp://pt851.wikidot.com/parkinsons-disease-cell-biology#LRRKhttp://pt851.wikidot.com/parkinsons-disease-cell-biology#LRRKhttp://pt851.wikidot.com/parkinsons-disease-cell-biology#LRRKhttp://pt851.wikidot.com/parkinsons-disease-cell-biology#LRRKhttp://pt851.wikidot.com/parkinsons-disease-cell-biology#LRRKhttp://www.ncbi.nlm.nih.gov/pubmed?term=Marsden%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Jenner%20P%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Schapira%20AH%5BAuthor%5D&cauthor=true&cauthor_uid=9470137http://www.ncbi.nlm.nih.gov/pubmed?term=Owen%20AD%5BAuthor%5D&cauthor=true&cauthor_uid=9470137