The pathophysiology of Parkinson's disease is

death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

rgic

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s as a result of changes in biological activity in the brain with respect to

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

(PD). There are several proposed mechanisms for

in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in

Lewy bodies Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside neurons affected by Parkinson's disease (PD), the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)) ...

, disruption of

autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...

, changes in cell metabolism or

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

l function,

neuroinflammation Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...

, and

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

(BBB) breakdown resulting in vascular leakiness.

Protein aggregation

The first major proposed cause of neuronal death in Parkinson's disease is the bundling, or oligomerization, of

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s. The protein

alpha-synuclein Alpha-synuclein (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the brai ...

has increased presence in the brains of Parkinson's Disease patients and, as α-synuclein is insoluble, it aggregates to form

(shown to left) in neurons. Traditionally, Lewy bodies were thought to be the main cause of cell death in Parkinson's disease; however, more recent studies suggest that Lewy bodies lead to other effects that cause cell death. Regardless, Lewy bodies are widely recognized as a

pathological Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...

marker of Parkinson's disease. Lewy bodies first appear in the

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (OF ...

medulla oblongata The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (involun ...

, and

pontine tegmentum The pontine tegmentum, or dorsal pons, is the dorsal part of the pons located within the brainstem. The ventral part or ventral pons is known as the basilar part of the pons, or basilar pons. Along with the dorsal surface of the medulla oblonga ...

; patients at this stage are asymptomatic. As the disease progresses, Lewy bodies develop in the

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra a ...

, areas of the

midbrain The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...

and basal

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...

, and in the

neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...

. This mechanism is substantiated by the facts that α-synuclein lacks toxicity when unable to form aggregates; that heat-shock proteins, which assist in refolding proteins susceptible to aggregation, beneficially affect PD when overexpressed; and that reagents which neutralize aggregated species protect neurons in cellular models of α-synuclein overexpression.

Alpha-synuclein Alpha-synuclein (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the brai ...

appears to be a key link between reduced

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...

and Parkinson's disease. Alpha-synuclein activates ATM ( ataxia-telangiectasia mutated), a major

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified ...

repair signaling

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

. Alpha-synuclein binds to breaks in double-stranded DNA and facilitates the DNA repair process of

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...

. It was suggested that cytoplasmic aggregation of alpha-synuclein to form

reduces its nuclear levels leading to decreased DNA repair, increased DNA double-strand breaks and increased

programmed cell death Programmed cell death (PCD) sometimes referred to as cell, or cellular suicide is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usual ...

Autophagy disruption

The second major proposed mechanism for neuronal death in Parkinson's disease,

, is a mechanism by which inner components of the cell are broken down and recycled for use. Autophagy has been shown to play a role in brain health, helping to regulate cellular function. Disruption of the autophagy mechanism can lead to several different types of diseases like Parkinson's disease. Autophagy dysfunction in Parkinson's disease has also been shown to lead to dysregulated mitochondria degradation.

Changes in cell metabolism

The third major proposed cause of cell death in Parkinson's disease involves the energy-generating

mitochondrion A mitochondrion () is an organelle found in the cell (biology), cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosine tri ...

organelle. In Parkinson's disease, mitochondrial function is disrupted, inhibiting energy production and resulting in death. The mechanism behind mitochondrial dysfunction in Parkinson's disease is hypothesized to be centered in the

PINK1 PTEN (gene), PTEN-induced kinase 1 (PINK1) is a mitochondrial Serine/threonine-specific protein kinase, serine/threonine-protein kinase encoded by the ''PINK1'' gene. It is thought to protect cells from stress-induced mitochondrion, mitochondria ...

and Parkin complex, having this been shown to drive autophagy of mitochondria (also known as

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 in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford ...

). PINK1 is a protein normally transported into the mitochondrion, but can also accumulate on the surface of impaired mitochondria. Accumulated PINK1 then recruits Parkin; Parkin initiates the breakdown of dysfunctional mitochondria, a mechanism that acts as a "quality control". In Parkinson's disease, the genes coding PINK1 and Parkin are thought to be mutated so as to impair the ability of these proteins to breakdown dysfunctional mitochondria, leading to abnormal mitochondrial function and

morphology Morphology, from the Greek and meaning "study of shape", may refer to: Disciplines *Morphology (archaeology), study of the shapes or forms of artifacts *Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies, ...

, and eventually cell death. Mitochondrial DNA (mtDNA) mutations have also been shown to accumulate with age indicating that susceptibility to this mechanism of neuronal death increases with age. Another mitochondrial-related mechanism for cell death in Parkinson's disease is the generation of

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(ROS).

ROS Ros or ROS or RoS may refer to: Organizations * Raggruppamento Operativo Speciale, the Anti-organized Crime Branch of the Italian Carabinieri * Registers of Scotland, a Scottish authority responsible for compiling and maintaining records * Repart ...

are highly reactive molecules that contain oxygen and can disrupt functions within the mitochondria and the rest of the cell. With increasing age, mitochondria lose their ability to remove ROS yet still maintain their production of ROS, causing an increase in net production of ROS and eventually cell death. As reviewed by Puspita et al. studies have demonstrated that in the

and the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

and

levels are likely involved in contributing to

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 ...

as well as PD symptoms.

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 ...

appears to have a role in mediating separate pathological events that together ultimately result in cell death in PD. Oxidative stress leading to cell death may be the common denominator underlying multiple processes. Oxidative stress causes oxidative DNA damage. Such damage is increased in the mitochondria of the

of PD patients and may lead to nigral neuronal cell death.

Neuroinflammation

The fourth proposed major mechanism of neuronal death in Parkinson's Disease,

, is generally understood for neurodegenerative diseases, however, specific mechanisms are not completely characterized for PD. One major cell type involved in neuroinflammation is the

microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...

. Microglia are recognized as the innate immune cells of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. Microglia actively survey their environment and change their cell morphology significantly in response to neural injury. Acute inflammation in the brain is typically characterized by rapid activation of microglia. During this period, there is no peripheral immune response. Over time, however, chronic inflammation causes the degradation of tissue and of the blood–brain barrier. During this time, microglia generate

and release signals to recruit peripheral immune cells for an inflammatory response. In addition,

are known to have two major states: M1, a state in which cells are activated and secrete

pro-inflammatory Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', ''d ...

factors; and M2, a state in which cells are deactivated and secrete

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...

factors. Microglia are usually in a resting state (M2), but in Parkinson's disease can enter M1 due to the presence of α-synuclein aggregates. The M1 microglia release pro-inflammatory factors which can cause motor neurons to die. In this case, dying cells can release factors to increase the activation of M1 microglia, leading to a

positive feedback loop Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop where the outcome of a process reinforces the inciting process to build momentum. As such, these forces can exacerbate the effects ...

which causes continually increasing cell death.

BBB breakdown

The fifth proposed major mechanism for cell death is the breakdown of the

(BBB). The BBB has three cell types which tightly regulate the flow of molecules in and out of the brain:

endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

pericyte Pericytes (formerly called Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood c ...

s, and

astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...

s. In neurodegenerative diseases, BBB breakdown has been measured and identified in specific regions of the brain, including the

in Parkinson's disease and

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

in Alzheimer's disease. Protein aggregates or cytokines from neuroinflammation may interfere with cell receptors and alter their function in the BBB. Most notably,

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

(VEGF) and

VEGF receptors VEGF receptors (VEGFRs) are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Depending on alternative splicing, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR). ...

are thought to be dysregulated in neurodegenerative diseases. The interaction between the VEGF protein and its receptors leads to cell proliferation, but is believed to be disrupted in Parkinson's disease and Alzheimer's disease. This then causes cells to stop growing and therefore, prevents new

capillary A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima (the inn ...

formation via

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

. Cell receptor disruption can also affect the ability for cells to adhere to one another with

adherens junction In cell biology, adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions and cell–matrix junctions in epithelial and endothelial tissues, usually more basa ...

s. Without new capillary formation, the existing capillaries break down and cells start to dissociate from each other. This in turn leads to the breakdown of gap junctions.

Gap junction Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites. Gap junctions were first described as ''close appositions'' alongside tight ...

s in endothelial cells in the BBB help prevent large or harmful molecules from entering the brain by regulating the flow of nutrients to the brain. However, as gap junctions break down, plasma proteins are able to enter in

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

the brain. This mechanism is also known as vascular leakiness, where capillary degeneration leads to blood and blood proteins "leaking" into the brain. Vascular leakiness can eventually cause neurons to alter their function and shift towards

apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...

behavior or cell death.

Impact on locomotion

Dopaminergic neurons are the most abundant type of neuron in the

, a part of the brain regulating motor control and learning.

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

is a

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

which modulates the activity of

motor neuron A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly o ...

s in the

. The activated motor neurons then transmit their signals, via

action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

, to motor neurons in the spinal cord. However, when a significant percentage of the motor neurons die (about 50-60%), this decreases dopamine levels by up to 80%. This inhibits the ability for neurons to generate and transmit a signal. This transmission inhibition ultimately causes the characteristic

Parkinsonian gait Parkinsonian gait (or festinating gait, from Latin ''festinare'' o hurry is the type of gait exhibited by patients with Parkinson's disease (PD). It is often described by people with Parkinson's as feeling like being stuck in place, when initiat ...

with symptoms such as hunched and slowed walking or tremors.

References

{{DEFAULTSORT:Pathophysiology of Parkinsons disease Parkinson's disease Programmed cell death