Parkinson’s disease affects Dopamine-rich neurons in Substantia Nigra
Parkinson’s disease is a common neurodegenerative disease in western world. PD brings to a progressive depigmentation of Substantia Nigra, caused by loss of Dopaminergic neurons, involved in some neuronal motory-patterns between Cortex, Basal Ganglia (mainly Striatum and Internal Globus Pallidum, involved in direct and indirect motory loops) and Thalamus, resulting in the clinical manifestations of PD. These include slowness of movement (bradykinesia), muscular rigidity, resting tremor and postural instability.
Our protein subject, DJ-1, if expressed, prevents oxidative damage which comes from hyperexpression of alpha-synuclein, stabilized by Dopamine, that is one of responsible of selectivity of DA cells in PD’s neurotoxicity. Although PD is considered as a sporadic disease, several genes have been identified as the cause of PD’s familiar forms. Here are analyzed PARK7 gene and his translate, DJ-1 protein, which have interactions with Chaperons proteins (mainly HSP70 and co chaperons) and Alpha-synuclein (gene SRCA, wich causes an autosomal dominant sporadic PD in case of mutations), both of them engaged in PD’s patogenesis. Understanding the molecular causes of Parkinson's disease.
Wood-Kaczmar A, Gandhi S, Et al
Role of protein chaperon Hsp70 in alpha-synuclein mediated neurotoxicity protection
Alpha-synuclein is a 140 amino-acids protein with an Alpha-helically folded N-terminal, a central hydrophobic core and an acidic domain located on C-terminal. It appears as a tetrameric protein of about 14×4 kDa with a great lipid binding capacity, involved in Dopamine storage and release. It is expressed ubiquitously in human brain, but mainly in Dopaminergic neurons and in CA1, CA3 regions of Hyppocampus (probably it is a protein involved in memory and learning pathways).
If the native tetramer of this protein is destabilized, we’ve alpha-syn misfolding and aggregation. Alpha-synuclein misfolded exposes some idrophobic domains wich interact with proteins and lipids in an aberrant way. The 'non A-beta component of Alzheimer disease amyloid plaque' domain (NAC domain) is involved in fibrils formation. The middle hydrophobic region forms the core of the filaments. The C-terminus may regulate aggregation and determine the diameter of the filaments. Molecular Chaperones in Parkinson's Disease - Present and Future.
Ebrahimi-Fakhari D, Wahlster L, Et al
Monomeric alpha-synuclein exists as a random structure. A variety of factors, including oxidative stressors (including environmental toxins), membrane association, altered pH, inhibition of proteolysis, alpha-synuclein mutations and multiplications, promote misfolding of alpha-synuclein and the formation of oligomers and/or protofibrils, which are rich in b-sheet structures. These oligomers form the basis of stable higher-order aggregates which can form amyloid-like fibrils those finally aggregate in Lewy's Bodies and Lewy's Neurites, which are intracellular aggregates of proteins positive for alpha-synuclein (the main component) and proteins ubiquitinated. Hsp70
can reverse the formation of higher-order aggregates. This is due to an overexpression of protein chaperones by a signaling cascade that involves HSF-1 (heat shock factor), that is normally sequestrated by Hsp90 in resting cell. During cellular stress, HSF-1 undergo to phosphorilation and trimerization and nuclear translocation, for inducing Hsp70’s gene transcription. Hsp70 can bind alpha-synuclein directly and can inhibit its neurotoxic fibrillization: it binds prefibrillar alpha-synuclein forms generating smaller and more soluble forms, that’s possible because alpha-synuclein, in the soluble form, present a central hydrophobic core which is bound to Hsp70. Hsp70 in that way discourage the formation of alpha-syn oligomers ,both intra and extracellular. Molecular Chaperones in Parkinson's Disease - Present and Future.
Ebrahimi-Fakhari D, Wahlster L, Et al
DJ-1 and its interaction with the alpha-syn and hsp70 pathways, in Autosomal Recessive Sporadical Early-Onset Parkinson Disease
After this introduction about the alpha-syn/hsp70 interaction in PD’s neurotoxicity, we can talk about PARK7 gene loss of function.
Gene PARK7 is located on chromosome 1. This gene is highly expressed in pancreas, kidney, skeletal muscle, liver, testis, heart and is detected at slightly lower levels in placenta and brain. in astrocytes, Sertoli cells, spermatogonia, spermatids and spermatozoa.
Homozygous loss-of-function mutations in the PARK7 (DJ- 1) gene are responsible for early-onset, L-DOPA-responsive parkinsonism. There are more than 10 PARK7 mutations that cause early-onset Parkinson disease. In some cases, a large portion of the PARK7 gene is deleted, and no functional DJ-1 protein is made. Other mutations lead to an abnormally small DJ-1 protein or change the amino acids sequence of the protein. The altered protein is unstable and does not function properly.
What’s the function of PARK7 transcript DJ-1? DJ-1 is a redox-sensitive protein that possesses antioxidant, RNA binding, antiapoptotic and chaperone properties found in Cytoplasm, Nucleus, Mitochondrion. Under normal conditions, it is located predominantly in the cytoplasm and, to a lesser extent, in the nucleus and mitochondrion. In response to oxidative stress it ranslocates to the mitochondrion and subsequently to the nucleus and exerts an increased cytoprotective effect against oxidative damage. It is detected in alpha syn inclusions .
In primary dopaminergic cell cultures, HSP70 upregulation is necessary for DJ-1-mediated suppression of a-syn aggregation.
It’s possible to find some correlations between DJ-1’s activity and alpha-synuclein/Hsp70’s pathways:
- The antiaggregation effect on a-syn is dependent on the oxidation state of DJ-1 at cysteine 106 (C106), although further oxidation of Cys and Met residues leads to a loss of its secondary structure and diminished chaperone activity. The oxidation of C106 to cysteine–sulphinic acid allows DJ-1 to translocate to mitochondria and this is necessary for neuroprotection, and proper mitochondria function. DJ-1 has also a direct cytosolic chaperone activity, to prevent proteins misfolding thanks to this 1Cys 106 oxidation. That’s the main cause why mutant DJ-1 is founded toghether with alpha-synuclein fibrils in Lewi’s Bodies. Pathogenesis of Parkinson's disease: emerging role of molecular chaperones.
Bandopadhyay R, de Belleroche J.
- In the human brain, DJ-1 is expressed ubiquitously. DJ-1 and its mutants colocalize with HSP70 in the cell cytosol. Upon exposure to oxidative stress it associates with the mitochondrial chaperone, and also it migrates to the cellular nucleus for up regulate Hsp70's mRNA expression. Furthermore Hsp70 is needed for the correct function of DJ-1. For this association DJ-1 gene expression appears to be related with Hsp70’s mRNA up-regulations after redox cellular stress and viceversa. This lead to an hypotesis of mutual interaction between both chaperon genes necessary for alpha-synuclein fibrils prevention. Pathogenesis of Parkinson's disease: emerging role of molecular chaperones.
Bandopadhyay R, de Belleroche J.
- for it’s property of oxidation-induced protein chaperon, DJ-1 have an important role in prevention of alpha-synuclein fibrils, both directly and indirectly by Hsp70’s mRNA upregulation.
- DJ-1 inactivation promotes α-syn aggregation and the related toxicity, and HSP70 is involved in the antioxidant response and in the regulation of α-syn fibril formation.
- DJ-1 can act as a chaperone directly or can up regulate Hsp70’s gene expression.
- Alpha-synuclein, by increasing cellular oxydative stress, inactivates DJ-1/Hsp70 chaperone system thanks to the inhibiting oxidations on DJ-1's Cys and Met (for its induction is necessary just oxidation of Cys 106). That's another feature that gives to SNCA gene's loss of function a Dominant face.