Parkinson's disease is the second most common neurodegenerative disease which affects almost 1% of the population above the age of 60. It is is characterized by loss of dopaminergic neurons in the striatum and substantia nigra, coupled with the formation of intracellular Lewy bodies in degenerating neurons. Recent evidence suggests endoplasmic reticulum stress as a common and prominent occurrence in the progression of Parkinson's disease pathogenesis in the affected human brain. One of the cellular defense mechanism to combat endoplasmic reticulum stress due to excessive protein accumulation is through activation of the unfolded protein response pathway. In this review we focus on the impact and role of this unfolded protein response as a causative factor of Parkinson's disease leading to neurodegeneration.
The synucleins are a family of presynaptic proteins that are abundant in neurons and include alpha-, ß-, and -synuclein. alpha-Synuclein (ASN) is involved in several neurodegenerative age-related disorders but its relevance in physiological aging is unknown. In the present study we investigated the expression of ASN mRNA and protein in the different brain parts of the adult (4-month-old) and aged (24-month-old) rats by using RT-PCR technique and Western blot, respectively. Our results indicated that mRNA expression and immunoreactivity of ASN is similar in brain cortex, hippocampus and striatum but markedly lower in cerebellum comparing to the other brain parts. Aging lowers ASN mRNA expression in striatum and cerebellum by about 40%. The immunoreactivity of ASN in synaptic plasma membranes (SPM) from aged brain cortex, hippocampus and cerebellum is significantly lower comparing to adult by 39%, 24% and 65%, respectively. ß-synuclein (BSN) was not changed in aged brain comparing to adult. Age-related alteration of ASN may affect the nerve terminals structure and function.
Sphingolipid deregulation may be an important factor of age-related neuronal stress vulnerability. Current data suggests potential links between sphingosine kinases (SphK1&2), their product sphingosine1-phosphate (S1P) and age-related protein conformation diseases. The aim of this study was to investigate a possible role of SphKs in alpha-synuclein (ASN) and amyloid beta (ABeta) precursor protein (APP) level and secretion. The studies were carried out using human SH-SY5Y neuroblastoma cell line stably transfected with the human gene for α-synuclein (ASNwt). Sphingosine kinase inhibitor (SKI) significantly increased ASN secretion in concentration-dependent manner. S1P also displayed similar influence. Neither compound exerted any significant effect on the ASN protein level. S1P may act via cell surface receptors or as an intracellular second messenger. The similar effect of S1P and SphK inhibitors on ASN secretion may suggest that the regulation of its release is critically dependent on the varied (intra)cellular targets of SphKs and downstream signaling pathways. We have found that stable human ASNwt expression in SH-SY5Y cells caused a three-fold, significant increase of the cellular APP level. In ASN-transfected cells S1P enhanced APP secretion and reduced its intracellular level. This could be linked to the recently reported effect of S1P on secretase beta activity. Inhibition of SphKs significantly decreased APP secretion. In summary our data indicates that endogenous ASN regulates APP level in SH-SY5Y cells and that sphingolipids play a crucial role in the secretion of ASN and APP. These processes may have significant impact on neuronal survival and health.
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