Parkin is a 465-
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
residue
Residue may refer to:
Chemistry and biology
* An amino acid, within a peptide chain
* Crop residue, materials left after agricultural processes
* Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...
E3 ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquiti ...
, a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans and mice is encoded by the ''PARK2''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Parkin plays a critical role in
ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
– the process whereby molecules are covalently labelled with
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
(Ub) and directed towards degradation in
proteasomes
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by whi ...
or
lysosomes
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...
. Ubiquitination involves the sequential action of three enzymes. First, an
E1 ubiquitin-activating enzyme binds to inactive Ub in
eukaryotic cells
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
via a
thioester
In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...
bond and mobilises it in an ATP-dependent process. Ub is then transferred to an
E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ligase.
There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.
In particular, parkin recognises proteins on the outer membrane of
mitochondria upon cellular insult and mediates the clearance of damaged mitochondria via
autophagy and proteasomal mechanisms.
Parkin also enhances cell survival by suppressing both mitochondria-dependent and -independent
apoptosis.
Mutations are associated with mitochondrial dysfunction, leading to neuronal death in
Parkinson’s disease
Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disea ...
and aberrant
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
in
tumourigenesis.
Structure
The precise function of parkin is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the
ubiquitin-proteasome system
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by whi ...
that mediates the targeting of proteins for
degradation
Degradation may refer to:
Science
* Degradation (geology), lowering of a fluvial surface by erosion
* Degradation (telecommunications), of an electronic signal
* Biodegradation of organic substances by living organisms
* Environmental degradatio ...
. Mutations in this gene are known to cause a familial form of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
known as autosomal recessive juvenile Parkinson's disease (AR-JP). Moreover, parkin is described to be necessary for mitophagy (autophagy of mitochondria).
However, how
loss of function
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
of the parkin protein leads to
dopaminergic
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
death in this disease is unclear. The prevailing
hypothesis
A hypothesis (plural hypotheses) is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can test it. Scientists generally base scientific hypotheses on previous obse ...
is that parkin helps degrade one or more proteins toxic to dopaminergic neurons. Putative substrates of parkin include
synphilin-1, CDC-rel1,
cyclin E
Cyclin E is a member of the cyclin family.
Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27K ...
, p38 tRNA synthase,
Pael-R,
synaptotagmin
Synaptotagmins (SYTs) constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 17 isoforms in the mammalian s ...
XI,
sp22 and parkin itself (see also
ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquit ...
). Additionally, parkin contains a
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
motif that binds
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to ...
s. Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins
CASK
A barrel or cask is a hollow cylindrical container with a bulging center, longer than it is wide. They are traditionally made of wooden staves and bound by wooden or metal hoops. The word vat is often used for large containers for liquids, u ...
and
PICK1
Protein Interacting with C Kinase - 1 is a protein that in humans is encoded by the ''PICK1'' gene.
Function
The protein encoded by this gene contains a PDZ domain, through which it interacts with protein kinase C, alpha ( PRKCA). This protein ...
.
![Parkin_v2](https://upload.wikimedia.org/wikipedia/commons/8/81/Parkin_v2.png)
Like other members of the RING-between-RING (RBR) family of E3 ligases, parkin possesses two
RING finger domain
In molecular biology, a RING (short for Really Interesting New Gene) finger domain is a protein structural domain of zinc finger type which contains a C3HC4 amino acid motif which binds two zinc cations (seven cysteines and one histidine arrange ...
s and an in-between-RING (IBR) region.
RING1 forms the binding site for E2 Ub-conjugating enzyme while RING2 contains the catalytic
cysteine residue (Cys431) that cleaves Ub off E2 and transiently binds it to E3 via a thioester bond.
Ub transfer is aided by neighbouring residues
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the d ...
His433, which accepts a proton from Cys431 to activate it, and
glutamate Glu444, which is involved in autoubiquitination.
Together these form the
catalytic triad
A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, acylases, li ...
, whose assembly is required for parkin activation.
Parkin also contains an
N-terminal Ub-like domain (Ubl) for specific
substrate recognition, a unique RING0 domain and a repressor (REP) region that tonically suppresses ligase activity.
Under resting conditions, the tightly coiled conformation of parkin renders it inactive, as access to the catalytic RING2 residue is
sterically blocked by RING0, while the E2 binding domain on RING1 is occluded by Ubl and REP.
Activating stimuli disrupt these interdomain interactions and induce parkin to collapse along the RING1-RING0 interface.
The active site of RING2 is drawn towards E2-Ub bound to RING1, facilitating formation of the Ub-thioester intermediate. Parkin activation requires
phosphorylation of
serine Ser65 in Ubl by
serine/threonine kinase
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prote ...
,
PINK1
PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the ''PINK1'' gene.
It is thought to protect cells from stress-induced mitochondrial dysfunction. PINK1 activity causes the parkin protein to bind to d ...
. Addition of a charged
phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosph ...
destabilises
hydrophobic interactions
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and exclude water#Properties, water molecules. The word hydrophobic literally means "water-fearing", and it describes the Segregation in m ...
between Ubl and neighbouring subregions, reducing autoinhibitory effects of this N-terminus domain.
Ser65Ala
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
s were found to ablate Ub-parkin binding whilst inhibiting parkin recruitment to damaged mitochondria.
PINK1 also phosphorylates Ub at Ser65, accelerating its discharge from E2 and enhancing its
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
for parkin.
Although structural changes following phosphorylation are uncertain,
crystallisation
Crystallization is the process by which solid forms, where the atoms or molecules are highly organized into a structure known as a crystal. Some ways by which crystals form are precipitating from a solution, freezing, or more rarely deposi ...
of parkin revealed a cationic pocket in RING0 formed by
lysine and
arginine residues Lys161, Arg163 and Lys211 that forms a putative phosphate binding site.
Considering that RING0 is unique to parkin and that its hydrophobic interface with RING1 buries Cys431 in inactive parkin,
targeting of phosphorylated Ub and/or Ubl towards this binding niche might be critical in dismantling autoinhibitory complexes during parkin activation.
Function
Mitophagy
Parkin plays a crucial role in
mitophagy Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmo ...
and clearance of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
.
Mitophagy is the elimination of damaged mitochondria in
autophagosomes, and is dependent on a
positive feedback
Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in th ...
cycle involving synergistic action of parkin and PINK1. Following severe cellular insult, rundown of mitochondrial
membrane potential prevents import of PINK1 into the
mitochondrial matrix
In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...
and causes it to aggregate on the outer mitochondrial membrane (OMM).
Parkin is recruited to mitochondria following
depolarisation
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
and phosphorylated by PINK1, which simultaneously phosphorylates Ub pre-conjugated to mitochondrial membrane proteins. PINK1 and Ub phosphorylation facilitate parkin activation and further assembly of mono- and poly-Ub chains.
Considering the proximity of these chains to PINK1, further phosphorylation of Ub at Ser65 is likely, potentiating parkin mobilisation and substrate ubiquitination in a
self-reinforcing cycle.
Parkin substrates include mitofusins Mfn1 and Mfn2, which are large
GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
s that promote mitochondria fusion into dynamic, tubular complexes that maximise efficiency of
oxidative phosphorylation.
However, upon mitochondrial damage, degradation of fusion proteins is necessary to separate them from the network via
mitochondrial fission and prevent the corruption of healthy mitochondria.
Parkin is therefore required before mitophagy as it ubiquinates Mfn1/2, labelling it for proteasomal degradation.
Proteomic
Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In ...
studies identified additional OMM proteins as parkin substrates, including fission protein FIS, its adaptor
TBC1D15 and
translocase
Translocase is a general term for a protein that assists in moving another molecule, usually across a cell membrane. These enzymes catalyze the movement of ions or molecules across membranes or their separation within membranes. The reaction is des ...
TOMM20
Mitochondrial import receptor subunit TOM20 homolog is a protein that in humans is encoded by the ''TOMM20'' gene. TOM20 is one of the receptor systems of the TOM complex (translocase of the outer membrane) in the outer mitochondrial membrane (OMM ...
and TOMM70 that facilitate movement of proteins such as PINK1 across OMM.
Miro (or
RHOT1/
RHOT2) is an OMM protein critical for
axonal transport
Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytopla ...
, and may be ubiquitinated and targeted towards proteasomal degradation by parkin.
Miro breakdown produced a marked decrease in migration of compromised mitochondria along
axons of mouse
hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
neurons,
reinforcing the importance of parkin in segregating defective mitochondria from their functioning counterparts and limiting the spatial spread of mitochondrial dysfunction, prior to autophagy.
During mitophagy, parkin targets
VDAC1, a voltage-gated anion channel that undergoes a conformational change upon mitochondrial membrane depolarisation, exposing a
cytosolic
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
domain for ubiquitination.
Silencing of VDAC1 expression in
HeLa
HeLa (; also Hela or hela) is an immortalized cell line used in scientific research. It is the oldest and most commonly used human cell line. The line is derived from cervical cancer cells taken on February 8, 1951, named after Henrietta ...
cells significantly reduced parkin recruitment to depolarised mitochondria and their subsequent clearance,
highlighting the critical role of VDAC1 as a selective marker of mitochondrial damage and instigator of mitophagy. Following Ub conjugation, parkin recruits autophagy receptors such as p62,
TAX1BP1
Tax1-binding protein 1 is a protein that in humans is encoded by the ''TAX1BP1'' gene.
Interactions
TAX1BP1 has been shown to interact with TNFAIP3 and TRAF6. TAX1BP1 binds to TNFAIP3
Tumor necrosis factor, alpha-induced protein 3 or A20 i ...
and
CALCOCO2
Calcium-binding and coiled-coil domain-containing protein 2 is a protein that in humans is encoded by the ''CALCOCO2'' gene.
The protein encoded by this gene is a subunit of nuclear domain 10 (ND10) bodies. ND10 bodies are nuclear domains appear ...
, facilitating assembly of autophagosomes that digest defective mitochondria.
Cell survival
Through activation of
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
signalling, parkin enhances survival and protects cells from stress-induced apoptosis. Upon cellular insult, parkin activates the catalytic HOIP
subunit of another E3 ligase LUBAC. HOIP triggers assembly of linear Ub
polymers
A polymer (; Greek '' poly-'', "many" + ''-mer'', "part")
is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic an ...
on NF-κB essential modulator (NEMO), potentiating
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of mitochondrial GTPase
OPA1.
Increased OPA1
translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
maintains
cristae
A crista (; plural cristae) is a fold in the inner membrane of a mitochondrion. The name is from the Latin for ''crest'' or ''plume'', and it gives the inner membrane its characteristic wrinkled shape, providing a large amount of surface area fo ...
structure and reduces
cytochrome C release from mitochondria, inhibiting
caspase-mediated apoptosis. Importantly, parkin activates HOIP with greater
potency
Potency may refer to:
* Potency (pharmacology), a measure of the activity of a drug in a biological system
* Virility
* Cell potency, a measure of the differentiation potential of stem cells
* In homeopathic dilutions, potency is a measure of how ...
than other LUBAC-associated factors HOIL-1 and sharpin,
meaning that parkin mobilisation significantly enhances tolerance to moderate
stressors.
Parkin possesses
DNA binding affinity
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...
and produces a
dose-dependent reduction in transcription and activity of
pro-apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
factor
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
.
Transfection
Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to des ...
of ''p53''
promoter with truncated versions of parkin into
SH-SY5Y neurons revealed that parkin directly binds to the ''p53'' promoter via its RING1 domain.
Conversely, parkin may be a transcriptional target of p53 in H460 lung cells, where it mediates the
tumour suppressor action of p53.
Considering its role in mitochondrial
homeostasis
In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
, parkin aids p53 in maintaining mitochondrial
respiration
Respiration may refer to:
Biology
* Cellular respiration, the process in which nutrients are converted into useful energy in a cell
** Anaerobic respiration, cellular respiration without oxygen
** Maintenance respiration, the amount of cellul ...
while limiting glucose uptake and
lactate production, thus preventing onset of the
Warburg effect during tumourigenesis.
Parkin further elevates cytosolic
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
levels and protects against
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, characterising it as a critical tumour suppressor with anti-
glycolytic and
antioxidant capabilities.
Clinical significance
Parkinson’s disease
PARK2 (
OMIM
Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM ...
br>
*602544 is the parkin gene that may cause a form of autosomal recessive juvenile Parkinson disease (
OMIM
Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM ...
br>
600116 due to a mutation in the parkin protein. This form of genetic mutation may be one of the most common known genetic causes of early-onset
Parkinson disease Parkinson may refer to:
*Parkinson (surname)
* ''Parkinson'' (TV series), British chat show, presented by Sir Michael Parkinson
*Parkinson, Queensland, suburb of Brisbane, Australia
*The Parkinsons (fl. early 20th century), American father-and-son ...
. In one study of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5%
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
mutations.
Patients with an autosomal recessive family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).
Patients with parkin mutations (PARK2) do not have
Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.
In humans,
loss-of-function mutations in parkin ''
PARK2'' gene have been implicated in 50% of inherited and 15% of juvenile-onset
sporadic forms of
Parkinson’s disease
Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disea ...
(PD).
While PD is traditionally regarded a late-onset
neurodegenerative
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
condition characterised by
alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
It is abundant in the brain, while smaller a ...
-enriched
Lewy bodies,
autosomal recessive PD due to parkin mutations is often early onset and lack the
ubiquitinated
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fou ...
protein deposits
pathognomonic Pathognomonic (rare synonym ''pathognomic'') is a term, often used in medicine, that means "characteristic for a particular disease". A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doub ...
for sporadic PD.
Parkin-mutant PD could also involve loss of
noradrenergic
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
neurons in the
locus coeruleus alongside the hallmark degeneration of
dopaminergic neurons in the
substantia nigra pars compacta (SNpc).
However, its symptoms resembles those of
idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...
PD, with patients presenting with resting
tremors,
postural instability
A balance disorder is a disturbance that causes an individual to feel unsteady, for example when standing or walking. It may be accompanied by feelings of giddiness, or wooziness, or having a sensation of movement, spinning, or floating. Balance ...
and
bradykinesia
Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...
.
While mitochondria are essential for ATP generation in any
eukaryotic cell
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacter ...
,
catecholaminergic
Catecholaminergic means "related to catecholamines". The catecholamine neurotransmitters include dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).
A catecholaminergic agent (or drug) is a chemical which functions to direc ...
neurons are particularly reliant on their proper function for clearance of reactive oxygen species produced by dopamine metabolism, and to supply high energy requirements of catecholamine synthesis.
Their susceptibility to oxidative damage and metabolic stress render catecholaminergic neurons vulnerable to
neurotoxicity
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
associated with aberrant regulation of mitochondrial activity, as is postulated to occur in both inherited and idiopathic PD. For example, enhanced oxidative stress in neurons,
skeletal muscle and
platelets, corresponding with reduced activity of
complex I
Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the ...
in the
electron transport chain were reported in PD patients,
while deletions in the
mitochondrial genome
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial ...
were found in the SNpc.
In accordance with its critical role in mitochondrial quality control, more than 120 pathogenic, PD-inducing mutations have been characterised on parkin.
Such mutations may be hereditary or stochastic and are associated with structural instability, reduced catalytic efficiency and aberrant substrate binding and ubiquitination.
Mutations can generally be categorised into three groups, depending on their location. Firstly, those clustered around Zn-coordinating residues on RING and IBR might compromise structural integrity and impair
catalysis
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
.
A second class of mutations, including Thr240Arg, affect residues in and around the E2 binding site and alter autoinhibition of RING1 by REP.
Finally, Cys431Phe and Gly430Asp mutations impair
ligase
In biochemistry, a ligase is an enzyme that can catalyze the joining (ligation) of two large molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the larger molecules or the enzym ...
activity at the
catalytic site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
and significantly reduce parkin function.
The discovery of numerous non-mitochondrial parkin substrates reinforces the importance parkin in neuronal homeostasis, beyond its role in mitochondrial regulation. Potent
neuroprotective
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
abilities of parkin in attenuating dopaminergic neurotoxicity, mitochondrial swelling and
excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...
were demonstrated in cell cultures over-expressing parkin,
although the existence of such mechanisms at physiological parkin levels ''in vivo'' is yet unconfirmed. Another parkin substrate, synphilin-1 (encoded by ''
SNCAIP
Synphilin-1 is a protein that in humans is encoded by the ''SNCAIP'' gene. ''SNCAIP'' stands for "synuclein, alpha interacting protein" and can be signified by SNCAP_HUMAN, synphilin 1, synuclein, alpha interacting protein (synphilin), and SYPH1.
...
''), is an alpha-synuclein interacting protein that is enriched in the core of Lewy bodies and ubiquitinated by parkin in a manner abolished by familial PD-associated mutations.
Parkin might promote aggregation of alpha-synuclein and synphilin-1 into Lewy bodies, which are conjugated to Lys63-linked poly-Ub chains and directed towards autophagic degradation.
Parkin mutations therefore inhibit this mechanism, leading to toxic accumulation of soluble proteins that overloads the proteasome. Protein aggregation triggers neuronal toxicity, whilst accounting for lack of ubiquitinated Lewy bodies in parkin-mutant PD. Similarly, native parkin reduces death of SH-SY5Y neurons by ubiquitinating other Lewy body constituents, such as the
p38 subunit of
aminoacyl-tRNA synthetase
An aminoacyl-tRNA synthetase (aaRS or ARS), also called tRNA-ligase, is an enzyme that attaches the appropriate amino acid onto its corresponding tRNA. It does so by catalyzing the transesterification of a specific cognate amino acid or its p ...
complex
and
far upstream element-binding protein 1 through addition of Lys48-linked poly-Ub chains and directing them towards proteasomal degradation. Parkin also influences axonal transport and
vesicle fusion Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles c ...
through ubiquitination of
tubulin
Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
and synaptotagmin XI (
SYT11) respectively, giving it a modulatory role in
synapse function.
Finally, parkin protects dopaminergic neurons from
cytotoxicity induced by PD-mimetic
6-OHDA, mediated by suppression of neuronal p53 expression and its downstream activation of the apoptotic cascade.
Several PD-associated parkin mutations are localised to RING1 and might impair its ability to bind and downregulate the ''p53'' promoter, leading to enhanced p53 expression.
Parkin-mutant PD patients also exhibit a four-fold elevation in p53
immunoreactivity
An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay ...
,
insinuating that failure of parkin-mediated anti-apoptosis might be involved in etiology of PD.
Tumourigenesis
Consistent with parkin’s potent anti-tumourigenic abilities, negative mutations and deletions have been reported in various tumours. For example, ''PARK2''
copy number
Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of d ...
was reduced in 85% of
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
samples while
lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...
s were associated with
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
deletion of ''PARK2'' at 6q25-q27 locus.
Parkin deficiency further diminished disease-free survival in infrared-irradiated mice without increasing tumour
incidence rate
In epidemiology, incidence is a measure of the probability of occurrence of a given medical condition in a population within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time peri ...
, suggesting that parkin deficiencies increase susceptibility to tumour-promoting events, rather than initiating tumour formation.
Similarly, chromosomal breaks in ''PARK2'' suppressed expression of
afadin scaffold protein
In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them i ...
in
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
, thereby comprising
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
integrity, enhancing
metastatic
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
potential and worsening overall
prognosis.
Haploinsufficient
Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...
''PARK2'' expression, either due to reduced copy number or DNA
hypermethylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
, was further detected in spontaneous
colorectal cancer where it accelerated all stages of intestinal
adenoma development in mouse models.
Parkin is therefore a potent modulator of tumour progression, without directly instigating tumourigenesis.
Interactions
Parkin (ligase) has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
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Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
It is abundant in the brain, while smaller a ...
,
*
CASK
A barrel or cask is a hollow cylindrical container with a bulging center, longer than it is wide. They are traditionally made of wooden staves and bound by wooden or metal hoops. The word vat is often used for large containers for liquids, u ...
,
*
CUL1,
*
FBXW7
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the ''FBXW7'' gene.
Function
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F ...
[ and
* ]GPR37
Probable G-protein coupled receptor 37 is a protein that in humans is encoded by the ''GPR37'' gene.
Interactions
GPR37 has been shown to interact with HSPA1A and Parkin (ligase).
GPR37 is a receptor for prosaposin. It was previously thought t ...
,
* HSPA1A
Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the ''HSPA1A'' gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfo ...
,[
* ]HSPA8
Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the ''HSPA8'' gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperon ...
,[
* Multisynthetase complex auxiliary component p38,]
* PDCD2
Programmed cell death protein 2 is a protein that in humans is encoded by the ''PDCD2'' gene.
Function
This gene encodes a nuclear protein expressed in a variety of tissues. The rat homolog, Rp8, is transiently expressed in immature thymocytes ...
,
* SEPT5
Septin-5 is a protein that in humans is encoded by the ''SEPT5'' gene.
Function
This gene is a member of the septin gene family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins a ...
,
* SNCAIP
Synphilin-1 is a protein that in humans is encoded by the ''SNCAIP'' gene. ''SNCAIP'' stands for "synuclein, alpha interacting protein" and can be signified by SNCAP_HUMAN, synphilin 1, synuclein, alpha interacting protein (synphilin), and SYPH1.
...
,
* STUB1
STUB1 (STIP1 homology and U-Box containing protein 1) is a human gene that codes for the protein CHIP (C terminus of HSC70-Interacting Protein).
Function
The CHIP protein encoded by this gene binds to and inhibits the ATPase activity of the cha ...
,
* SYT11, and
* Ubiquitin C
Polyubiquitin-C is a protein encoded by the ''UBC'' gene in humans. Polyubiquitin-C is one of the sources of ubiquitin, along with UBB, UBA52, and RPS27A.
''UBC'' gene is one of the two stress-regulated polyubiquitin genes (''UBB'' and ''UBC' ...
.
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Parkin Type of Juvenile Parkinson Disease
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