Pathophysiology of Parkinson's disease

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Neuronal Death in the PD brain
Blausen 0704 ParkinsonsDisease.png
A brain without and with Parkinson's Disease compared in Substantia Nigra

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death 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, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness. [1]

Contents

Protein aggregation

A brain tissue with Lewy bodies. Lewy Body alphaSynuclein.jpg
A brain tissue with Lewy bodies.

The first major proposed cause of neuronal death in Parkinson's disease is the bundling, or oligomerization, of proteins. The protein alpha-synuclein has increased presence in the brains of Parkinson's Disease patients and, as α-synuclein is insoluble, it aggregates to form Lewy bodies (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. [2] Regardless, Lewy bodies are widely recognized as a pathological marker of Parkinson's disease.

Lewy bodies first appear in the olfactory bulb, medulla oblongata, and pontine tegmentum; patients at this stage are asymptomatic. As the disease progresses, Lewy bodies develop in the substantia nigra, areas of the midbrain and basal forebrain, and in the neocortex.

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. [3]

Alpha-synuclein appears to be a key link between reduced DNA repair and Parkinson’s disease. [4] Alpha-synuclein activates ATM (ataxia-telangiectasia mutated), a major DNA damage repair signaling kinase. Alpha-synuclein binds to breaks in double-stranded DNA and facilitates the DNA repair process of non-homologous end joining. [5] It was suggested [5] that cytoplasmic aggregation of alpha-synuclein to form Lewy bodies reduces its nuclear levels leading to decreased DNA repair, increased DNA double-strand breaks and increased programmed cell death of neurons.

Autophagy disruption

An image illustrating Autophagy. Autophagy diagram PLoS Biology.tif
An image illustrating Autophagy.

The second major proposed mechanism for neuronal death in Parkinson's disease, autophagy, is a mechanism by which inner components of the cell are broken down and recycled for use. [2] [6] 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. [6] [7]

Autophagy dysfunction in Parkinson's disease has also been shown to lead to dysregulated mitochondria degradation. [8]

Changes in cell metabolism

A simplified illustration of energy production in a mitochondrion. Aerobic mitochondria process.png
A simplified illustration of energy production in a mitochondrion.

The third major proposed cause of cell death in Parkinson's disease involves the energy-generating mitochondrion organelle. In Parkinson's disease, mitochondrial function is disrupted, inhibiting energy production and resulting in death. [9] [10]

The mechanism behind mitochondrial dysfunction in Parkinson's disease is hypothesized to be centered in the PINK1 and Parkin complex, having this been shown to drive autophagy of mitochondria (also known as mitophagy). [9] [10] [11] 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". [9] 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, and eventually cell death. [9] [10] Mitochondrial DNA (mtDNA) mutations have also been shown to accumulate with age [12] 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 (ROS). [12] [13] ROS 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. [12] [13]

As reviewed by Puspita et al. [14] studies have demonstrated that in the mitochondria and the endoplasmic reticulum, alpha-synuclein and dopamine levels are likely involved in contributing to oxidative stress as well as PD symptoms. Oxidative stress appears to have a role in mediating separate pathological events that together ultimately result in cell death in PD. [14] 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 substantia nigra of PD patients and may lead to nigral neuronal cell death. [15] [16]


Neuroinflammation

Microglia(green) interacting with neurons(red). Microglia and neurons.jpg
Microglia(green) interacting with neurons(red).

The fourth proposed major mechanism of neuronal death in Parkinson's Disease, neuroinflammation, is generally understood for neurodegenerative diseases, however, specific mechanisms are not completely characterized for PD. [17] One major cell type involved in neuroinflammation is the microglia. Microglia are recognized as the innate immune cells of the central nervous system. 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 reactive oxygen species and release signals to recruit peripheral immune cells for an inflammatory response.

In addition, microglia are known to have two major states: M1, a state in which cells are activated and secrete pro-inflammatory factors; and M2, a state in which cells are deactivated and secrete anti-inflammatory factors. [18] 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 which causes continually increasing cell death. [17]

BBB breakdown

An image depicting blood-brain barrier shape and function. Blood-brain barrier transport en.png
An image depicting blood–brain barrier shape and function.

The fifth proposed major mechanism for cell death is the breakdown of the blood–brain barrier (BBB). The BBB has three cell types which tightly regulate the flow of molecules in and out of the brain: endothelial cells, pericytes, and astrocytes. In neurodegenerative diseases, BBB breakdown has been measured and identified in specific regions of the brain, including the substantia nigra in Parkinson's disease and hippocampus in Alzheimer's disease. [19] Protein aggregates or cytokines from neuroinflammation may interfere with cell receptors and alter their function in the BBB. [19] [20] Most notably, vascular endothelial growth factor (VEGF) and VEGF receptors 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. [20] [21] This then causes cells to stop growing and therefore, prevents new capillary formation via angiogenesis. Cell receptor disruption can also affect the ability for cells to adhere to one another with adherens junctions. [22]

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. [23] [24] Gap junctions 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 the brain. [23] 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 behavior or cell death.

Impact on locomotion

An image depicting Parkinsonian gait. Paralysis agitans-Male Parkinson's victim-1892.jpg
An image depicting Parkinsonian gait.

Dopaminergic neurons are the most abundant type of neuron in the substantia nigra, a part of the brain regulating motor control and learning. Dopamine is a neurotransmitter which modulates the activity of motor neurons in the central nervous system. The activated motor neurons then transmit their signals, via action potential, to motor neurons in the spinal cord. [25] However, when a significant percentage of the motor neurons die (about 50-60%), this decreases dopamine levels by up to 80%. [10] This inhibits the ability for neurons to generate and transmit a signal. This transmission inhibition ultimately causes the characteristic Parkinsonian gait with symptoms such as hunched and slowed walking or tremors.

Related Research Articles

<span class="mw-page-title-main">Substantia nigra</span> Structure in the basal ganglia of the brain

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 appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.

<span class="mw-page-title-main">Lewy body</span> Spherical inclusion commonly found in damaged neurons

Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias, and some other disorders. They are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P).

<span class="mw-page-title-main">Alpha-synuclein</span> Protein found in humans

Alpha-synuclein(aSyn) 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.

<span class="mw-page-title-main">Parkin (protein)</span>

Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the PARK2 gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub) and directed towards degradation in proteasomes or lysosomes. Ubiquitination involves the sequential action of three enzymes. First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester 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.

<span class="mw-page-title-main">Neuroprotection</span> Relative preservation of neuronal structure and/or function

Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

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 lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">Beta-synuclein</span> Protein-coding gene in the species Homo sapiens

Beta-synuclein is a protein that in humans is encoded by the SNCB gene.

<span class="mw-page-title-main">PINK1</span> Protein-coding gene in the species Homo sapiens

PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.

<span class="mw-page-title-main">VPS35</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.

<span class="mw-page-title-main">Brain mitochondrial carrier protein 1</span> Protein-coding gene in the species Homo sapiens

Brain mitochondrial carrier protein 1 is a protein that in humans is encoded by the SLC25A14 gene.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

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 Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

Parkinson's disease (PD) is a complicated neurodegenerative disease that progresses over time and is marked by bradykinesia, tremor, and stiffness. As the condition worsens, some patients may also experience postural instability. Parkinson's disease (PD) is primarily caused by the gradual degeneration of dopaminergic neurons in the region known as the substantia nigra along with other monoaminergic cell groups throughout the brainstem, increased activation of microglia, and the build-up of Lewy bodies and Lewy neurites, which are proteins found in surviving dopaminergic neurons.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

Parthanatos is a form of programmed cell death that is distinct from other cell death processes such as necrosis and apoptosis. While necrosis is caused by acute cell injury resulting in traumatic cell death and apoptosis is a highly controlled process signalled by apoptotic intracellular signals, parthanatos is caused by the accumulation of Poly(ADP ribose) (PAR) and the nuclear translocation of apoptosis-inducing factor (AIF) from mitochondria. Parthanatos is also known as PARP-1 dependent cell death. PARP-1 mediates parthanatos when it is over-activated in response to extreme genomic stress and synthesizes PAR which causes nuclear translocation of AIF. Parthanatos is involved in diseases that afflict hundreds of millions of people worldwide. Well known diseases involving parthanatos include Parkinson's disease, stroke, heart attack, and diabetes. It also has potential use as a treatment for ameliorating disease and various medical conditions such as diabetes and obesity.

<span class="mw-page-title-main">Mitochondria associated membranes</span> Cellular structure

Mitochondria-associated membranes (MAMs) represent regions of the endoplasmic reticulum (ER) which are reversibly tethered to mitochondria. These membranes are involved in import of certain lipids from the ER to mitochondria and in regulation of calcium homeostasis, mitochondrial function, autophagy and apoptosis. They also play a role in development of neurodegenerative diseases and glucose homeostasis.

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

Ted M. Dawson is an American neurologist and neuroscientist. He is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and Director of the Institute for Cell Engineering at Johns Hopkins University School of Medicine. He has joint appointments in the Department of Neurology, Neuroscience and Department of Pharmacology and Molecular Sciences.

Sonia Gandhi is a British physician and neuroscientist who leads the Francis Crick Institute neurodegeneration laboratory. She holds a joint position at the UCL Queen Square Institute of Neurology. Her research investigates the molecular mechanisms that give rise to Parkinson's disease. During the COVID-19 pandemic, Gandhi was involved with the epidemiological investigations and testing efforts at the Francis Crick Institute.

<span class="mw-page-title-main">Animal models of Parkinson's disease</span> Models used in Parkinsons disease research

Animal models of Parkinson's disease are essential in the research field and widely used to study Parkinson's disease. Parkinson's disease is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of the dopamine neurons in the brain, results in motor dysfunction, ultimately causing the four cardinal symptoms of PD: tremor, rigidity, postural instability, and bradykinesia. It is the second most prevalent neurodegenerative disease, following Alzheimer's disease. It is estimated that nearly one million people could be living with PD in the United States.

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