IS CELL DEATH IN PARKINSONíS DISEASE REALLY APOPTOSIS?
Ozansoy M, Basak AN*
*Corresponding Author: A. Nazli Basak, Bogaziçi University, Department of Molecular Biology and Genetics, 34342, Bebek, Istanbul, Turkey; Tel.: +90-212-359-66-79; Fax: +90-212-287-24-68; E-mail: basak@boun.edu.tr
page: 3

PARKINSONíS DISEASE

Parkinsonís Disease (PD) is a common, late-onset, progressive neurodegenerative disorder, characterized by a combination of motor symptoms (resting tremor, brady­kinesia, rigidity and postural instability). It is the most common neurodegenerative disorder after Alzheimerís Disease (AD), occurring in 2% of the the population older than 65 years with prevalence increasing with age. A rath­er selective degeneration of dopaminergic neurons of the substantia nigra pars compacta leads to deficiency of dopa­mine in the striatal projection areas of these neurons. Characteristic eosinophilic inclusions (Lewy bodies) are present in surviving dopaminergic neurons and, although less abundantly, elsewhere in the brain, and are considered to be the neuropathologic hallmark of PD [1,2].

      Parkinsonís Disease presents mainly as a sporadic condition, that is, in the absence of any genetic linkage, but rarely, it can also arise as a simple Mendelian trait, for a variety of genes. However, all of the identified mutations and loci seem to affect only a relatively small number of families. Although sporadic and familial PD may differ in several aspects, they share the same dramatic depletion in brain dopamine. The six genes so far linked to familial PD encode the proteins Parkin, DJ-1, PINK1 (PTEN-induced kinase 1), leucine-rich repeat kinase 2 (Dardarin), UCH-L1 (ubiquitin carboxyl terminal hydrolase L1), and a-synu­clein. Of these, Parkin, UCH-L1, DJ-1 and a-synuclein have some relationship to the ubiquitin/proteasome system (UPS). Loss-of-function in Parkin (an E3 ligase)and in DJ-1, causes autosomal recessive juvenile Parkinsonism. A mutation in UCH-L1 (which has ubiquitin hydrolase and ligase activities, and stabilizes free mono ubiquitin) causes autosomal dominant PD. a-Synuclein (a small presynaptic protein without a well-defined function), becomes a sub­strate for Parkin upon O-glycosylation. Missense muta­tions in, and whole-gene triplication of its gene, cause autosomal dominant PD. Point mutations in PINK1 cause autosomal recessive PD (Table 1).

      In sporadic PD, decreased proteasomal activity has been reported in the midbrain. Because Parkin, UCH-L1, 26S proteasome, a-synuclein and ubiquitin are compo­nents of Lewy bodies, it has been assumed that insufficient function of UPS can be important in the pathogenesis of PD. It has been argued that the neuronal death in PD starts with otherwise healthy dopaminergic neurons, being af­fected by an etiological factor, such as a mutation in the genes (mentioned above), and that subsequently a cascade of deleterious factors is set in motion by a combination of free radicals, mitochondrial dysfunction, excitotoxicity, neuroinflammation and apoptosis [3].

 

Table 1. Chromosomal locations of the genes and their inheritance patterns in familial Parkinsonís Disease cases described to date [1-3,20,21]

 

 

Chromosomal

Location

Inheritance

Pattern

Gene

4q21-q23

AD

a-synuclein

6q25.2-q17

AR

Parkin

4p14

AD

UCH-L1

1p35-p36

AR

PINK-1

Ip36

AR

DJ-1

12p11.2-q12.1

AR

Dardarin

 

AD: autosomal dominant; AR: autosomal recessive.

 




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